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BROCADE3: a challenge to the treatment paradigm in BRCA breast cancer? The Lancet. Oncology Telli, M. L. 2020
View details for DOI 10.1016/S1470-2045(20)30431-9

View details for PubMedID 32861274
Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet (London, England) Mittendorf, E. A., Zhang, H., Barrios, C. H., Saji, S., Jung, K. H., Hegg, R., Koehler, A., Sohn, J., Iwata, H., Telli, M. L., Ferrario, C., Punie, K., Penault-Llorca, F., Patel, S., Duc, A. N., Liste-Hermoso, M., Maiya, V., Molinero, L., Chui, S. Y., Harbeck, N. 2020; 396 (10257): 1090?1100
Abstract

Preferred neoadjuvant regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. IMpassion031 compared efficacy and safety of atezolizumab versus placebo combined with nab-paclitaxel followed by doxorubicin plus cyclophosphamide as neoadjuvant treatment for early-stage TNBC.This double-blind, randomised, phase 3 study enrolled patients in 75 academic and community sites in 13 countries. Patients aged 18 years or older with previously untreated stage II-III histologically documented TNBC were randomly assigned (1:1) to receive chemotherapy plus intravenous atezolizumab at 840 mg or placebo every 2 weeks. Chemotherapy comprised of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks, which was then followed by surgery. Stratification was by clinical breast cancer stage and programmed cell death ligand 1 (PD-L1) status. Co-primary endpoints were pathological complete response in all-randomised (ie, all randomly assigned patients in the intention-to-treat population) and PD-L1-positive (ie, patients with PD-L1-expressing tumour infiltrating immune cells covering ?1% of tumour area) populations. This study is registered with ClinicalTrials.gov (NCT03197935), Eudra (CT2016-004734-22), and the Japan Pharmaceutical Information Center (JapicCTI-173630), and is ongoing.Between July 7, 2017, and Sept 24, 2019, 455 patients were recruited and assessed for eligibility. Of the 333 eligible patients, 165 were randomly assigned to receive atezolizumab plus chemotherapy and 168 to placebo plus chemotherapy. At data cutoff (April 3, 2020), median follow-up was 20�6 months (IQR 8�7-24�9) in the atezolizumab plus chemotherapy group and 19�8 months (8�1-24�5) in the placebo plus chemotherapy group. Pathological complete response was documented in 95 (58%, 95% CI 50-65) patients in the atezolizumab plus chemotherapy group and 69 (41%, 34-49) patients in the placebo plus chemotherapy group (rate difference 17%, 95% CI 6-27; one-sided p=0�0044 [significance boundary 0�0184]). In the PD-L1-positive population, pathological complete response was documented in 53 (69%, 95% CI 57-79) of 77 patients in the atezolizumab plus chemotherapy group versus 37 (49%, 38-61) of 75 patients in the placebo plus chemotherapy group (rate difference 20%, 95% CI 4-35; one-sided p=0�021 [significance boundary 0�0184]). In the neoadjuvant phase, grade 3-4 adverse events were balanced and treatment-related serious adverse events occurred in 37 (23%) and 26 (16%) patients, with one patient per group experiencing an unrelated grade 5 adverse event (traffic accident in the atezolizumab plus chemotherapy group and pneumonia in the placebo plus chemotherapy group).In patients with early-stage TNBC, neoadjuvant treatment with atezolizumab in combination with nab-paclitaxel and anthracycline-based chemotherapy significantly improved pathological complete response rates with an acceptable safety profile.F Hoffmann-La Roche/Genentech.

View details for DOI 10.1016/S0140-6736(20)31953-X

View details for PubMedID 32966830
Association of Tumor Infiltrating Lymphocytes with Homologous Recombination Deficiency and BRCA1/2 Status in Patients with Early Triple-Negative Breast Cancer: A Pooled Analysis. Clinical cancer research : an official journal of the American Association for Cancer Research Telli, M. L., Chu, C., Badve, S. S., Vinayak, S., Silver, D. P., Isakoff, S. J., Kaklamani, V., Gradishar, W., Stearns, V., Connolly, R. M., Ford, J. M., Gruber, J. J., Adams, S., Garber, J., Tung, N., Neff, C., Bernhisel, R., Timms, K. M., Richardson, A. L. 2019
Abstract

Patients with triple-negative breast cancer (TNBC) with homologous recombination deficient tumors achieve significantly higher pathologic complete response (pCR) rates when treated with neoadjuvant platinum-based therapy. Tumor infiltrating lymphocytes (TILs) are prognostic and predictive of chemotherapy benefit in early stage TNBC. The relationship between TILs, BRCA1/2 mutation status and Homologous Recombination Deficiency (HRD) status in TNBC remains unclear.We performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HRD status (Myriad Genetics) and tumor BRCA1/2 mutation status. Further, the relationship between pathologic response assessed using the residual cancer burden (RCB) index and HRD status with adjustment for TILs was evaluated.Among 161 patients, stromal TIL (sTIL) density was not significantly associated with HRD status (p=0.107) or tumor BRCA1/2 mutation status (p=0.391). In multivariate analyses, sTIL density (OR 1.23, 95% CI 0.94-1.61, p=0.139) was not associated with pCR, but was associated with RCB 0/I status (OR 1.62, 95% CI 1.20-2.28, p=0.001). HRD was significantly associated with both pCR (OR 12.09, 95% CI 4.11-44.29, p= 7.82 x10-7) and RCB 0/I (OR 10.22, 95% CI 4.11-28.75, p= 1.09 x10-7) in these models.In patients with TNBC treated with neoadjuvant platinum-based therapy, TIL density was not significantly associated with either tumor BRCA1/2 mutation status or HRD status. In this pooled analysis, HRD and sTIL density were independently associated with treatment response, with HRD status being the strongest predictor.

View details for DOI 10.1158/1078-0432.CCR-19-0664

View details for PubMedID 31796517
Open-Label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. JAMA oncology Vinayak, S., Tolaney, S. M., Schwartzberg, L., Mita, M., McCann, G., Tan, A. R., Wahner-Hendrickson, A. E., Forero, A., Anders, C., Wulf, G. M., Dillon, P., Lynce, F., Zarwan, C., Erban, J. K., Zhou, Y., Buerstatte, N., Graham, J. R., Arora, S., Dezube, B. J., Telli, M. L. 2019
Abstract

Poly(adenosine diphosphate-ribose) polymerase inhibitor and anti-programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC).To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC.This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019.Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle.The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response?plus?partial response?plus?stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival.Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n?=?47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected.Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation.ClinicalTrials.gov identifier: NCT02657889.

View details for DOI 10.1001/jamaoncol.2019.1029

View details for PubMedID 31194225

View details for PubMedCentralID PMC6567845
Future of checkpoint blockade in triple-negative breast cancer: combination strategies to lead the way. Annals of oncology : official journal of the European Society for Medical Oncology Telli, M. L., Vinayak, S. 2019
View details for DOI 10.1093/annonc/mdz040

View details for PubMedID 30753266
Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer. Breast cancer research and treatment Telli, M. L., Stover, D. G., Loi, S., Aparicio, S., Carey, L. A., Domchek, S. M., Newman, L., Sledge, G. W., Winer, E. P. 2018
Abstract

Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit.We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection.Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise.HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

View details for DOI 10.1007/s10549-018-4807-x

View details for PubMedID 29736741
A Phase II Study of Talazoparib After Platinum or Cytotoxic Nonplatinum Regimens in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO). Clinical cancer research : an official journal of the American Association for Cancer Research Turner, N. C., Telli, M. L., Rugo, H. S., Mailliez, A., Ettl, J., Grischke, E. M., Mina, L. A., Balma�a, J., Fasching, P. A., Hurvitz, S. A., Wardley, A. M., Chappey, C., Hannah, A. L., Robson, M. E. 2018
Abstract

To assess talazoparib activity in germline BRCA1/2 mutation carriers with advanced breast cancer (aBC).ABRAZO (NCT02034916) was a two-cohort, two-stage, phase II study of talazoparib (1 mg/day) in germline BRCA mutation carriers with a response to prior platinum with no progression on or within 8 weeks of the last platinum dose (cohort 1) or ?3 platinum-free cytotoxic regimens (cohort 2) for aBC. Primary endpoint was confirmed objective response rate (ORR) by independent radiological assessment.We enrolled 84 patients (cohort 1, n = 49; cohort 2, n = 35) from May 2014 to February 2016. Median age was 50 (range, 31-75) years. Triple-negative breast cancer incidence was 59% (cohort 1) and 17% (cohort 2). Median number of prior cytotoxic regimens for aBC was two and four, respectively. Confirmed ORR was 21% (95% CI, 10 to 35) (cohort 1) and 37% (95% CI, 22 to 55) (cohort 2). Median duration of response was 5.8 and 3.8 months, respectively. Confirmed ORR was 23% (BRCA1), 33% (BRCA2), 26% (TNBC) and 29% (hormone receptor positive). The most common allgrade adverse events (AEs) included anemia (52%), fatigue (45%), and nausea (42%). Talazoparib-related AEs led to drug discontinuation in three (4%) patients. In an exploratory analysis, longer platinum-free interval was associated with higher response rate in cohort 1 (0% ORR with interval <8 weeks; 47% ORR with interval >6 months).Talazoparib exhibited promising antitumor activity in patients with aBC and germline BRCA mutation.

View details for PubMedID 30563931
Tumor BRCA1 Reversion Mutation Arising During Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance. Clinical cancer research : an official journal of the American Association for Cancer Research Afghahi, A., Timms, K. M., Vinayak, S., Jensen, K. C., Kurian, A. W., Carlson, R. W., Chang, P., Schackmann, E. A., Hartman, A., Ford, J. M., Telli, M. L. 2017
Abstract

In germline BRCA1 or BRCA2 (BRCA1/2) mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed BRCA1/2-mutant breast cancer patients with poor response to neoadjuvant platinum-based therapy.PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin and iniparib in patients with stage I-IIIA triple-negative or BRCA1/2 mutation-associated breast cancer (n=80). All patients underwent comprehensive BRCA1/2 genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy, BRCA1/2 status was re-sequenced in the residual surgical breast tumor tissue.Nineteen patients had a deleterious germline BRCA1/2 mutation and 4 had moderate residual disease at surgery. BRCA1/2 sequencing of residual tissue was performed on three patients. These patients had BRCA1 1479delAG, 3374insGA and W1712X mutations, respectively, with loss of heterozygosity at these loci in the pre-treatment tumors. In the first case, a new BRCA1 mutation was detected in the residual disease. This resulted in a 14 amino acid deletion and restoration of the BRCA1 reading frame. A local relapse biopsy four months later revealed the identical reversion mutation, and the patient subsequently died of metastatic breast cancer.We report a BRCA1 reversion mutation in a newly diagnosed triple-negative breast cancer patient that developed over 18 weeks of platinum-based neoadjuvant therapy. This was associated with poor therapy response, early relapse and death.

View details for DOI 10.1158/1078-0432.CCR-16-2174

View details for PubMedID 28087643
Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clinical cancer research Telli, M. L., Timms, K. M., Reid, J., Hennessy, B., Mills, G. B., Jensen, K. C., Szallasi, Z., Barry, W. T., Winer, E. P., Tung, N. M., Isakoff, S. J., Ryan, P. D., Greene-Colozzi, A., Gutin, A., Sangale, Z., Iliev, D., Neff, C., Abkevich, V., Jones, J. T., Lanchbury, J. S., Hartman, A., Garber, J. E., Ford, J. M., Silver, D. P., Richardson, A. L. 2016; 22 (15): 3764-3773
Abstract

BRCA1/2 mutated and some sporadic triple negative breast cancers (TNBCs) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed based on loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST).We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score {greater than or equal to}42 or BRCA1/2 mutation, with response to platinum-based therapy.In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted Residual Cancer Burden score of 0 or 1 (RCB 0/1) and pathologic complete response (pCR) (OR=4.96, p=0.0036; OR=6.52, p=0.0058). HR deficiency remained a significant predictor of RCB 0/1 when adjusted for clinical variables (OR=5.86, p=0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/1 and pCR (OR=10.18, p=0.0011; OR=17.00, p=0.0066). In a multivariable model of RCB 0/1, HR deficiency retained significance when clinical variables were included (OR=12.08, p=0.0017). When restricted to BRCA1/2 non-mutated tumors, response was higher in patients with high HRD scores: RCB 0/1 p=0.062, pCR p=0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/1 p=0.0039, pCR p=0.018 in the neoadjuvant cisplatin trials.HR deficiency identifies TNBC tumors, including BRCA1/2 non-mutated tumors more likely to respond to platinum-containing therapy.

View details for DOI 10.1158/1078-0432.CCR-15-2477

View details for PubMedID 26957554
Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity NATURE MEDICINE Burridge, P. W., Li, Y. F., Matsa, E., Wu, H., Ong, S., Sharma, A., Holmstrom, A., Chang, A. C., Coronado, M. J., Ebert, A. D., Knowles, J. W., Telli, M. L., Witteles, R. M., Blau, H. M., Bernstein, D., Altman, R. B., Wu, J. C. 2016; 22 (5): 547-556
Abstract

Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.

View details for DOI 10.1038/nm.4087

View details for PubMedID 27089514
Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105. Journal of clinical oncology Telli, M. L., Jensen, K. C., Vinayak, S., Kurian, A. W., Lipson, J. A., Flaherty, P. J., Timms, K., Abkevich, V., Schackmann, E. A., Wapnir, I. L., Carlson, R. W., Chang, P., Sparano, J. A., Head, B., Goldstein, L. J., Haley, B., Dakhil, S. R., Reid, J. E., Hartman, A., Manola, J., Ford, J. M. 2015; 33 (17): 1895-1901
Abstract

This study was designed to assess efficacy, safety, and predictors of response to iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation-associated breast cancer.This single-arm phase II study enrolled patients with stage I to IIIA (T ? 1 cm) estrogen receptor-negative (? 5%), progesterone receptor-negative (? 5%), and human epidermal growth factor receptor 2-negative or BRCA1/2 mutation-associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m(2) intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies.Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021).Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted.

View details for DOI 10.1200/JCO.2014.57.0085

View details for PubMedID 25847929
Insight or confusion: survival after response-guided neoadjuvant chemotherapy in breast cancer JOURNAL OF CLINICAL ONCOLOGY Telli, M. L. 2013; 31 (29): 3613-5
PARP inhibitors in cancer: moving beyond BRCA LANCET ONCOLOGY Telli, M. L. 2011; 12 (9): 827-828
View details for DOI 10.1016/S1470-2045(11)70236-4

View details for Web of Science ID 000294293500003

View details for PubMedID 21862406
Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Gradishar, W. J., Anderson, B. O., Abraham, J., Aft, R., Agnese, D., Allison, K. H., Blair, S. L., Burstein, H. J., Dang, C., Elias, A. D., Giordano, S. H., Goetz, M. P., Goldstein, L. J., Isakoff, S. J., Krishnamurthy, J., Lyons, J., Marcom, P. K., Matro, J., Mayer, I. A., Moran, M. S., Mortimer, J., O'Regan, R. M., Patel, S. A., Pierce, L. J., Rugo, H. S., Sitapati, A., Smith, K. L., Smith, M. L., Soliman, H., Stringer-Reasor, E. M., Telli, M. L., Ward, J. H., Young, J. S., Burns, J. L., Kumar, R. 2020; 18 (4): 452?78
Abstract

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

View details for DOI 10.6004/jnccn.2020.0016

View details for PubMedID 32259783
Genetics of triple-negative breast cancer: Implications for patient care. Current problems in cancer Afghahi, A., Telli, M. L., Kurian, A. W. ; 40 (2-4): 130?40
Abstract

Patients with triple-negative breast cancer (TNBC), defined as lacking expression of the estrogen and progesterone receptors (ER/PR) and amplification of the HER2 oncogene, often have a more aggressive disease course than do patients with hormone receptor-positive breast cancer, including higher rates of visceral and central nervous system metastases, early cancer recurrences and deaths. Triple-negative breast cancer is associated with a young age at diagnosis and both African and Ashkenazi Jewish ancestry, the latter due to three common founder mutations in the highly penetrant cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2). In the past decade, there has been a surge both in genetic testing technology and in patient access to such testing. Advances in genetic testing have enabled more rapid and less expensive commercial sequencing than could be imagined only a few years ago. Massively parallel, next-generation sequencing allows the simultaneous analysis of many different genes. Studies of TNBC patients in the current era have revealed associations of TNBC with mutations in several moderate penetrance breast cancer susceptibility genes, including PALB2, BARD1, BRIP1, RAD51C and RAD51D. Interestingly, many of these genes, like BRCA1/2, are involved in homologous recombination DNA double-stranded repair. In this review, we summarize the current understanding of pathogenic germline gene mutations associated with TNBC and the early detection and prevention strategies for women at risk of developing this high-risk breast cancer subtype. Furthermore, we discuss recent the advances in targeted therapies for TNBC patients with a hereditary predisposition, including the role of poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2 mutation-associated breast cancers.

View details for PubMedID 28340968
Human Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Breast Cancer Patients. Circulation Kitani, T., Ong, S. G., Lam, C. K., Rhee, J. W., Zhang, J. Z., Oikonomopoulos, A., Ma, N., Tian, L., Lee, J., Telli, M. L., Witteles, R. M., Sharma, A., Sayed, N., Wu, J. C. 2019
Abstract

Molecular targeted chemotherapies have been shown to significantly improve cancer patient outcomes, but often cause cardiovascular side effects that limit their use and impair patients' quality of life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype compared to cardiotoxicity induced by conventional chemotherapies.We employed the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) platform to determine the underlying cellular mechanisms in trastuzumab-induced cardiac dysfunction. We assessed the effects of trastuzumab on structural and functional properties in iPSC-CMs from healthy individuals and performed RNA-sequencing (RNA-seq) to further examine the effect of trastuzumab on iPSC-CMs. We also generated iPSCs from patients receiving trastuzumab and examined whether patients' phenotype could be recapitulated in vitro using patient-specific iPSC-CMs.We found that clinically relevant doses of trastuzumab significantly impaired the contractile and calcium handling properties of iPSC-CMs without inducing cardiomyocyte death or sarcomeric disorganization. RNA-seq and subsequent functional analysis revealed mitochondrial dysfunction and altered cardiac energy metabolism pathway as primary causes of trastuzumab-induced cardiotoxic phenotype. Human iPSC-CMs generated from patients who received trastuzumab and experienced severe cardiac dysfunction were more vulnerable to trastuzumab treatment, compared to iPSC-CMs generated from patients who did not experience cardiac dysfunction following trastuzumab therapy. Importantly, metabolic modulation with AMPK activators could avert the adverse effects induced by trastuzumab.Our results indicate that alterations in cellular metabolic pathways in cardiomyocytes could be a key mechanism underlying the development of cardiac dysfunction following trastuzumab therapy; therefore, targeting the altered metabolism may be a promising therapeutic approach for trastuzumab-induced cardiac dysfunction.

View details for PubMedID 30866650
NCCN Guidelines Updates: Breast Cancer. Journal of the National Comprehensive Cancer Network : JNCCN Telli, M. L., Gradishar, W. J., Ward, J. H. 2019; 17 (5.5): 552?55
Abstract

Advances in molecular testing have ushered in the new era of precision medicine. The 2018 publication of the TAILORx trial helped refine the use of genetic expression assays, specifically the 21-gene recurrence score, in assigning patients to endocrine therapy alone or with chemotherapy. The NCCN Guidelines for Breast Cancer explore the clinical applications of this study. The algorithm for managing the axilla in early breast cancer has been further refined, based on the presence or absence of clinical evidence of lymph node involvement. Ovarian suppression has been validated as the optimal approach in higher risk premenopausal women, based on updated analysis of the SOFT and TEXT pivotal trials. In the metastatic setting, the NCCN Guidelines further reinforce the benefit of the CDK4/6 inhibitors, extending the "preferred" recommendation to all the available agents in metastatic disease. Options in triple-negative breast cancer now include, for the first time, an immunotherapeutic agent.

View details for DOI 10.6004/jnccn.2019.5006

View details for PubMedID 31117035
NCCN Guidelines Insights: Breast Cancer, Version 3.2018. Journal of the National Comprehensive Cancer Network : JNCCN Goetz, M. P., Gradishar, W. J., Anderson, B. O., Abraham, J., Aft, R., Allison, K. H., Blair, S. L., Burstein, H. J., Dang, C., Elias, A. D., Farrar, W. B., Giordano, S. H., Goldstein, L. J., Isakoff, S. J., Lyons, J., Marcom, P. K., Mayer, I. A., Moran, M. S., Mortimer, J., O'Regan, R. M., Patel, S. A., Pierce, L. J., Reed, E. C., Rugo, H. S., Sitapati, A., Smith, K. L., Smith, M. L., Soliman, H., Telli, M. L., Ward, J. H., Young, J. S., Shead, D. A., Kumar, R. 2019; 17 (2): 118?26
Abstract

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor-positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

View details for PubMedID 30787125
Decision Making About Genetic Testing Among Women With a Personal and Family History of Breast Cancer. Journal of oncology practice Scott, D., Friedman, S., Telli, M. L., Kurian, A. W. 2019: JOP1900221
Abstract

To understand genetic testing use and decision making among patients with high genetic risk.A survey of breast cancer survivors was administered online by a hereditary cancer nonprofit organization, Facing Our Risk of Cancer Empowered, from October 2017 to March 2018.Of 1,322 respondents, 46% had breast cancer at age < 45 years, 61% had a first-degree relative with cancer, and 84% underwent genetic testing, of whom 56% had a risk-associated pathogenic variant. Most (86%; 95% CI, 84% to 88%) tested respondents were very satisfied with their testing decision, versus 34% (95% CI, 27% to 41%) of untested respondents. Factors that encouraged testing included relatives' cancer risk (75%; 95% CI, 73% to 78%), clinicians' recommendations (68%; 95% CI, 66% to 71%), and potential treatment implications (67%; 95% CI, 64% to 69%). Factors that discouraged testing included insurance concerns (14%; 95% CI, 12% to 16%), cost (14%; 95% CI, 12% to 16%), and discrimination (9%; 95% CI, 7% to 11%). Thirty-nine percent (95% CI, 36% to 41%) recalled hearing from a clinician that genetic discrimination is illegal. Respondents often recalled clinicians informing them about inheritance patterns (65%; 95% CI, 62% to 67%), surgical implications (65%; 95% CI, 63% to 68%), and other cancer risks (66%; 95% CI, 63% to 68%) but less often that results could have potential implications for clinical trial eligibility (38%; 95% CI, 36% to 42%) or targeted therapies (14%; 95% CI, 12% to 16%). Patients who had genetic counseling were twice as likely to recall clinicians informing them about all queried topics. Results did not vary by diagnosis year.Among patients with high genetic risk, clinicians' recommendations, potential treatment implications, and protections against discrimination were motivating factors to undergo genetic testing, but fewer than half recalled clinicians providing all this information, and this did not improve over time. Clinicians influence testing decisions and should inform patients about legal protections and treatment implications.

View details for DOI 10.1200/JOP.19.00221

View details for PubMedID 31613719
Induced Pluripotent Stem Cell-Based Cancer Vaccines. Frontiers in immunology Ouyang, X., Telli, M. L., Wu, J. C. 2019; 10: 1510
Abstract

Over a century ago, it was reported that immunization with embryonic/fetal tissue could lead to the rejection of transplanted tumors in animals. Subsequent studies demonstrated that vaccination of embryonic materials in animals induced cellular and humoral immunity against transplantable tumors and carcinogen-induced tumors. Therefore, it has been hypothesized that the shared antigens between tumors and embryonic/fetal tissues (oncofetal antigens) are the key to anti-tumor immune responses in these studies. However, early oncofetal antigen-based cancer vaccines usually utilize xenogeneic or allogeneic embryonic stem cells or tissues, making it difficult to tease apart the anti-tumor immunity elicited by the oncofetal antigens vs. graft-vs.-host responses. Recently, one oncofetal antigen-based cancer vaccine using autologous induced pluripotent stem cells (iPSCs) demonstrated marked prophylactic and therapeutic potential, suggesting critical roles of oncofetal antigens in inducing anti-tumor immunity. In this review, we present an overview of recent studies in the field of oncofetal antigen-based cancer vaccines, including single peptide-based cancer vaccines, embryonic stem cell (ESC)- and iPSC-based whole-cell vaccines, and provide insights on future directions.

View details for DOI 10.3389/fimmu.2019.01510

View details for PubMedID 31338094

View details for PubMedCentralID PMC6628907
Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Cruz, C., Llop-Guevara, A., Garber, J. E., Arun, B. K., Perez Fidalgo, J. A., Lluch, A., Telli, M. L., Fernandez, C., Kahatt, C., Galmarini, C. M., Soto-Matos, A., Alfaro, V., Perez de la Haza, A., Domchek, S. M., Antolin, S., Vahdat, L., Tung, N. M., Lopez, R., Arribas, J., Vivancos, A., Baselga, J., Serra, V., Balmana, J., Isakoff, S. J. 2018: JCO2018786558
Abstract

PURPOSE: This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance.PATIENTS AND METHODS: Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors.RESULTS: ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts.CONCLUSION: Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

View details for PubMedID 30240327
Outcomes Following Neoadjuvant Chemotherapy for Breast Cancer in Women Aged 40 Years and Younger: Impact of Pathologic Nodal Response. Journal of the National Comprehensive Cancer Network : JNCCN Kozak, M. M., Jacobson, C. E., von Eyben, R., Pollom, E. L., Telli, M., Horst, K. C. 2018; 16 (7): 845?50
Abstract

Purpose: We sought to evaluate whether pathologic nodal response was predictive of outcomes in women aged ?40 years with breast cancer treated with neoadjuvant chemotherapy (NAC). Methods: A total of 220 patients treated with NAC between 1991 and 2015 were retrospectively reviewed. Pathologic complete response (pCR) was defined as no evidence of residual invasive tumor in the breast and lymph nodes (LNs) (ypT0/Tis ypN0); partial response if there was no tumor in the LNs but residual tumor in the breast (ypT+ ypN0) or residual tumor in the LNs (ypT0/Tis ypN+); and limited response if there was residual tumor in both the breast and the LNs (ypT+ ypN+). Kaplan-Meier and Cox proportional hazards analyses were performed to identify factors predictive for overall survival (OS). Results: A total of 155 patients were included. Following NAC, 39 patients (25.2%) achieved pCR, 57 (36.8%) achieved a partial response (either ypT+ ypN0 or ypT0/Tis ypN+), and 59 (38.1%) had a limited response. A total of 22 patients (14.2%) experienced local failure, 20 (12.9%) experienced regional failure, and 59 (38.1%) experienced distant failure. Median OS for patients who achieved pCR was not reached, and was significantly worse for patients who had residual disease in the breast and/or LNs (P<.001). No difference in OS was seen among patients who had residual disease in the breast alone versus those who remained LN-positive (97 vs 83 months, respectively; P=.25). Subset analysis did not reveal differences in OS based on year of treatment or cN1 disease at the time of initial diagnosis. Conclusions: Women aged ?40 years who achieved pCR had excellent outcomes; however, those who achieved a pathologic response in the LNs but had residual disease in the breast continued to have outcomes similar to those who remained LN-positive.

View details for DOI 10.6004/jnccn.2018.7022

View details for PubMedID 30006427
Higher Absolute Lymphocyte Counts Predict Lower Mortality from Early-Stage Triple-Negative Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Afghahi, A., Purington, N., Han, S. S., Desai, M., Pierson, E., Mathur, M. B., Seto, T., Thompson, C. A., Rigdon, J., Telli, M. L., Badve, S. S., Curtis, C., West, R. B., Horst, K., Gomez, S. L., Ford, J. M., Sledge, G. W., Kurian, A. W. 2018
Abstract

Tumor-infiltrating lymphocytes (TILs) in pre-treatment biopsies are associated with improved survival in triple-negative breast cancer (TNBC). We investigated whether higher peripheral lymphocyte counts are associated with lower breast cancer-specific mortality (BCM) and overall mortality (OM) in TNBC.Data on treatments and diagnostic tests from electronic medical records of two healthcare systems were linked with demographic, clinical, pathologic, and mortality data from the California Cancer Registry. Multivariable regression models adjusted for age, race/ethnicity, socioeconomic status, cancer stage, grade, neoadjuvant/adjuvant chemotherapy use, radiotherapy use, and germline BRCA1/2 mutations were used to evaluate associations between absolute lymphocyte count (ALC), BCM and OM. For a subgroup with TILs data available, we explored the relationship between TILs and peripheral lymphocyte counts.1,463 Stage I-III TNBC patients were diagnosed from 2000-2014; 1113 (76%) received neoadjuvant/adjuvant chemotherapy within one year of diagnosis. Of 759 patients with available ALC data, 481 (63.4%) were ever lymphopenic (minimum ALC <1.0 K/?L). On multivariable analysis, higher minimum ALC, but not absolute neutrophil count, predicted lower OM (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.16-0.35) and BCM (HR: 0.19, CI: 0.11-0.34). Five-year probability of BCM was 15% for patients who were ever lymphopenic versus 4% for those who were not. An exploratory analysis (N=70) showed a significant association between TILs and higher peripheral lymphocyte counts during neoadjuvant chemotherapy.Higher peripheral lymphocyte counts predicted lower mortality from early-stage, potentially curable TNBC, suggesting that immune function may enhance the effectiveness of early TNBC treatment.

View details for PubMedID 29581131
Paclitaxel With Inhibitor of Apoptosis Antagonist, LCL161, for Localized Triple-Negative Breast Cancer, Prospectively Stratified by Gene Signature in a Biomarker-Driven Neoadjuvant Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Bardia, A., Parton, M., K�mmel, S., Est�vez, L. G., Huang, C. S., Cort�s, J., Ruiz-Borrego, M., Telli, M. L., Martin-Martorell, P., L�pez, R., Beck, J. T., Ismail-Khan, R., Chen, S. C., Hurvitz, S. A., Mayer, I. A., Carreon, D., Cameron, S., Liao, S., Baselga, J., Kim, S. B. 2018: JCO2017748392
Abstract

There are currently no targeted therapies approved for triple-negative breast cancer (TNBC). A tumor necrosis factor ? ( TNF?)-based gene expression signature (GS) predictive of sensitivity to LCL161, inhibitor of apoptosis antagonist, was translated into a clinical assay and evaluated in a neoadjuvant trial.Women with localized TNBC (T2/N0-2/M0) were prospectively stratified by GS status and randomly assigned (1:1) to receive oral LCL161 (1,800 mg once per week) and intravenous paclitaxel (80 mg/m2 once per week; combination arm) or paclitaxel alone (control arm) for 12 weeks, followed by surgery. The primary objective was to determine whether neoadjuvant LCL161 enhances efficacy of paclitaxel, defined by > 7.5% increase in the pathologic complete response (pCR, breast) rate, stratified by GS.Of 209 patients enrolled (207 with valid GS scores), 30.4% had GS-positive TNBC. In the GS-positive group, pCR was higher in the combination versus the control arm (38.2% v 17.2%), with 88.8% posterior probability of > 7.5% increase in pCR. However, in the GS-negative group, the pCR was lower in the combination group (5.6% v 16.4%), with 0% posterior probability of > 7.5% increase in pCR. A higher incidence of grade 3 or 4 adverse events in the combination arm included neutropenia (24.5%) and diarrhea (5.7%). Overall, 19 patients (18.1%) in the combination arm discontinued treatment because of adverse events, including pyrexia (n = 5), pneumonia (n = 4), and pneumonitis (n = 4), versus five patients (4.9%) in the control arm.This neoadjuvant trial provides evidence supporting a biomarker-driven targeted therapy approach for selected patients with GS-positive TNBC and demonstrates the utility of a neoadjuvant trial for biomarker validation and drug development, but also highlights toxicity risk. Future neoadjuvant clinical trials should carefully weigh these considerations for targeted therapy development in biomarker-defined TNBC.

View details for PubMedID 30235087
A four-gene decision tree signature classification of triple-negative breast cancer: Implications for targeted therapeutics. Molecular cancer therapeutics Quist, J., Mirza, H., Cheang, M. C., Telli, M. L., O'Shaughnessy, J., Lord, C. J., Tutt, A. N., Grigoriadis, A. 2018
Abstract

The molecular complexity of triple-negative breast cancers (TNBCs) provides a challenge for patient management. We set out to characterise this heterogeneous disease by combining transcriptomics and genomics data, with the aim of revealing convergent pathway dependencies with the potential for treatment intervention. A Bayesian algorithm was used to integrate molecular profiles in two TNBC cohorts, followed by validation using five independent cohorts (n = 1,168), including three clinical trials. A four-gene decision tree signature was identified which robustly classified TNBCs into six subtypes. All four genes in the signature (EXO1, TP53BP2, FOXM1 and RSU1) are associated with either genomic instability, malignant growth, or treatment response. One of the six subtypes, MC6, encompassed the largest proportion of tumours (~50%) in early diagnosed TNBCs. In TNBC patients with metastatic disease, the MC6 proportion was reduced to 25%, and was independently associated with a higher response rate to platinum-based chemotherapy. In TNBC cell line data, platinum-sensitivity was recapitulated, and a sensitivity to the inhibition of the phosphatase PPM1D was revealed. Molecularly, MC6-TNBCs displayed high levels of telomeric allelic imbalances, enrichment of CD4+ and CD8+ immune signatures, and reduced expression of genes negatively regulating the mitogen-activated protein kinase (MAPK) signalling pathway. These observations suggest that our integrative classification approach may identify TNBC patients with discernible and theoretically pharmacologically tractable features that merit further studies in prospective trials.

View details for PubMedID 30305342
Quality of life with talazoparib after platinum or multiple cytotoxic non-platinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations: patient-reported outcomes from the ABRAZO phase 2 trial. European journal of cancer (Oxford, England : 1990) Hurvitz, S. A., Quek, R. G., Turner, N. C., Telli, M. L., Rugo, H. S., Mailliez, A., Ettl, J., Grischke, E., Mina, L. A., Balma�a, J., Fasching, P. A., Bhattacharyya, H., Hannah, A. L., Robson, M. E., Wardley, A. M. 2018; 104: 160?68
Abstract

Talazoparib (1�mg/day) exhibited promising efficacy and safety in patients with advanced breast cancer during ABRAZO (NCT02034916); this study evaluated patient-reported outcomes (PROs).ABRAZO is a two-cohort, two-stage, phase 2 study of talazoparib in patients with advanced breast cancer after a response to prior platinum-based therapy (cohort 1 [C1], n�=�49) or ?3 platinum-free cytotoxic-based regimens (cohort 2 [C2], n�=�35). PROs were assessed on day 1 (baseline), every 6 weeks for an initial 24 weeks, and every 12 weeks thereafter until progression, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and its breast cancer module, QLQ-BR23.Global health status/quality of life (GHS/QoL) was maintained from baseline across all time points for both C1 and C2. For C1 and C2, median time to deterioration (TTD) of GHS/QoL (95% confidence interval [CI]) was 2.8 (2.1, 3.0) and 5.5 (4.2, 5.7) months, respectively. Median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1-3.1 months and 4.2-5.6 months, respectively; median TTD for all QLQ-BR23 symptom�scales ranged 2.6-4.0 months and 4.2-5.6 months, respectively. There were no statistically significant differences in estimated overall change from baseline in the GHS/QoL scale for both cohorts (C1: -2.6 [95% CI, -7.8, 2.5]; C2: 1.2 [95% CI, -5.5, 8.0]). Significant overall improvements in the breast symptoms and arm symptoms�and the future perspective of patients in C1 and C2 were observed, despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2).Despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2), patients in both C1 and C2 reported significant overall improvements in their breast symptoms, arm symptoms�and future perspective, and their GHS/QoL was maintained from baseline.

View details for PubMedID 30359909
Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Denduluri, N., Chavez-MacGregor, M., Telli, M. L., Eisen, A., Graff, S. L., Hassett, M. J., Holloway, J. N., Hurria, A., King, T. A., Lyman, G. H., Partridge, A. H., Somerfield, M. R., Trudeau, M. E., Wolff, A. C., Giordano, S. H. 2018: JCO2018788604
Abstract

Purpose To update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. Methods An Expert Panel conducted targeted systematic literature reviews guided by a signals approach to identify new, potentially practice-changing data that might translate to revised practice recommendations. Results The Expert Panel reviewed phase III trials that evaluated adjuvant capecitabine after completion of standard preoperative anthracycline- and taxane-based combination chemotherapy by patients with early-stage breast cancer HER2-negative breast cancer with residual invasive disease at surgery; the addition of 1 year of adjuvant pertuzumab to combination chemotherapy and trastuzumab for patients with early-stage, HER2-positive breast cancer; and the use of neratinib as extended adjuvant therapy for patients after combination chemotherapy and trastuzumab-based adjuvant therapy with early-stage, HER2-positive breast cancer. Recommendations Patients with early-stage HER2-negative breast cancer with pathologic, invasive residual disease at surgery following standard anthracycline- and taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant capecitabine. Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer. Clinicians may use extended adjuvant therapy with neratinib to follow trastuzumab in patients with early-stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea, and diarrhea prophylaxis must be used. Additional information can be found at www.asco.org/breast-cancer-guidelines .

View details for PubMedID 29787356
Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer Breast Cancer Research and Treatment Telli, M. L., Stover, D., Loi, S., Aparicio, S., Carey, L. A., Domchek, S. M., Newman, L., Sledge, G. W., Winer, E. P. 2018: in press
Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update Journal of Clinical Oncology Denduluri , N., Chavez-MacGregor, M., Telli, M. L., Eisen, A., Graff, S., Hassett, M., Holloway, J., Hurria, A., King, T., Lyman, G., Partridge, A., Somerfield, M., Trudeau, M., Wolff, A., Giorando, S. 2018: In press
Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Gradishar, W. J., Anderson, B. O., Balassanian, R., Blair, S. L., Burstein, H. J., Cyr, A., Elias, A. D., Farrar, W. B., Forero, A., Giordano, S. H., Goetz, M. P., Goldstein, L. J., Isakoff, S. J., Lyons, J., Marcom, P. K., Mayer, I. A., McCormick, B., Moran, M. S., O'Regan, R. M., Patel, S. A., Pierce, L. J., Reed, E. C., Salerno, K. E., Schwartzberg, L. S., Sitapati, A., Smith, K. L., Smith, M. L., Soliman, H., Somlo, G., Telli, M. L., Ward, J. H., Kumar, R., Shead, D. A. 2018; 16 (3): 310?20
Abstract

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

View details for DOI 10.6004/jnccn.2018.0012

View details for PubMedID 29523670
Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kornblum, N., Zhao, F., Manola, J., Klein, P., Ramaswamy, B., Brufsky, A., Stella, P. J., Burnette, B., Telli, M., Makower, D. F., Cheema, P., Truica, C. I., Wolff, A. C., Soori, G. S., Haley, B., Wassenaar, T. R., Goldstein, L. J., Miller, K. D., Sparano, J. A. 2018: JCO2017769331
Abstract

Purpose The mammalian target of rapamycin inhibitor everolimus targets aberrant signaling through the PI3K/AKT/mammalian target of rapamycin pathway, a mechanism of resistance to anti-estrogen therapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that everolimus plus the selective ER downregulator fulvestrant would be more efficacious than fulvestrant alone in ER-positive metastatic breast cancer resistant to aromatase inhibitor (AI) therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase II study included 131 postmenopausal women with ER-positive, human epidermal growth factor receptor 2-negative, AI-resistant metastatic breast cancer randomly assigned to fulvestrant (500 mg days 1 and 15 of cycle 1, then day 1 of cycles 2 and beyond) plus everolimus or placebo. The study was designed to have 90% power to detect a 70% improvement in median progression-free survival from 5.4 months to 9.2 months. Secondary end points included objective response and clinical benefit rate (response or stable disease for at least 24 weeks). Prophylactic corticosteroid mouth rinses were not used. Results The addition of everolimus to fulvestrant improved the median progression-free survival from 5.1 to 10.3 months (hazard ratio, 0.61 [95% CI, 0.40 to 0.92]; stratified log-rank P = .02), indicating that the primary trial end point was met. Objective response rates were similar (18.2% v 12.3%; P = .47), but the clinical benefit rate was significantly higher in the everolimus arm (63.6% v 41.5%; P = .01). Adverse events of all grades occurred more often in the everolimus arm, including oral mucositis (53% v 12%), fatigue (42% v 22%), rash (38% v 5%), anemia (31% v. 6%), diarrhea (23% v 8%), hyperglycemia (19% v 5%), hypertriglyceridemia (17% v 3%), and pneumonitis (17% v 0%), although grade 3 to 4 events were uncommon. Conclusion Everolimus enhances the efficacy of fulvestrant in AI-resistant, ER-positive metastatic breast cancer.

View details for PubMedID 29664714
Assessing treatment response in triple-negative breast cancer from quantitative image analysis in perfusion magnetic resonance imaging. Journal of medical imaging (Bellingham, Wash.) Banerjee, I., Malladi, S., Lee, D., Depeursinge, A., Telli, M., Lipson, J., Golden, D., Rubin, D. L. 2018; 5 (1): 011008
Abstract

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is sensitive but not specific to determining treatment response in early stage triple-negative breast cancer (TNBC) patients. We propose an efficient computerized technique for assessing treatment response, specifically the residual tumor (RT) status and pathological complete response (pCR), in response to neoadjuvant chemotherapy. The proposed approach is based on Riesz wavelet analysis of pharmacokinetic maps derived from noninvasive DCE-MRI scans, obtained before and after treatment. We compared the performance of Riesz features with the traditional gray level co-occurrence matrices and a comprehensive characterization of the lesion that includes a wide range of quantitative features (e.g., shape and boundary). We investigated a set of predictive models ([Formula: see text]) incorporating distinct combinations of quantitative characterizations and statistical models at different time points of the treatment and some area under the receiver operating characteristic curve (AUC) values we reported are above 0.8. The most efficient models are based on first-order statistics and Riesz wavelets, which predicted RT with an AUC value of 0.85 and pCR with an AUC value of 0.83, improving results reported in a previous study by [Formula: see text]. Our findings suggest that Riesz texture analysis of TNBC lesions can be considered a potential framework for optimizing TNBC patient care.

View details for PubMedID 29134191

View details for PubMedCentralID PMC5668126
Patterns of Distant Failure by Intrinsic Breast Cancer Subtype in Premenopausal Women Treated With Neoadjuvant Chemotherapy. Clinical breast cancer Kozak, M. M., Jacobson, C. E., von Eyben, R., Walck, E., Pollom, E. L., Telli, M., Horst, K. C. 2018
Abstract

To identify patterns of distant failure (DF) in premenopausal women receiving neoadjuvant chemotherapy (NAC) for breast cancer.Premenopausal patients treated with NAC between 2005 and 2015 at a single institution were retrospectively reviewed. Timing and location of local, regional, and distant metastases were described. Predictors for DF and overall survival (OS) were analyzed.Of 225 patients, there were 24 (10.7%) local, 30 (13.3%) regional, and 63 (28.0%) distant recurrences. Cumulative incidence of DF was higher in patients younger than age 40 (P�= .01), in those with residual tumor size > 2 cm (P�< .0001), in those with positive lymph nodes after NAC (P�= .0003), and in those without pathologic complete response (P�< .0001). Cumulative incidence of brain metastases was most common in patients with human epidermal growth factor receptor 2 (HER2)-positive disease (P�= .05). Time from development of metastatic disease to death varied by breast cancer subtype (P�= .019), as did 5-year OS (P�= .024). Women with HER2-positive and triple-negative disease had the highest incidence of brain metastases and the shortest time from development of metastases to death. On multivariable analysis, luminal B subtype (P�= .025), pathologic complete response (P�= .0014), young age (P�= .0008), lack of hormone therapy (P�<�.0001), lymphovascular space involvement (P�< .0001), and pathologic size of the primary tumor (P�< .0001) were all significant predictors for DF.Patterns of DF after NAC in premenopausal women vary by breast cancer subtype, with DF more common than locoregional failure. Young age remains an independent poor prognostic factor, and OS differs by breast cancer subtype.

View details for PubMedID 29843987
Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation-associated breast cancer. Breast cancer research and treatment Telli, M. L., Hellyer, J., Audeh, W., Jensen, K. C., Bose, S., Timms, K. M., Gutin, A., Abkevich, V., Peterson, R. N., Neff, C., Hughes, E., Sangale, Z., Jones, J., Hartman, A. R., Chang, P. J., Vinayak, S., Wenstrup, R., Ford, J. M. 2018; 168 (3): 625?30
Abstract

Defects in the homologous recombination (HR) DNA repair pathway sensitize tumors to therapeutics that target this pathway. A significant proportion of triple-negative breast cancers (TNBC) carry HR defects. The HRD assay is highly associated with sensitivity to neoadjuvant platinum-based chemotherapy in TNBC. Standard chemotherapy consists of some combination of an anthracycline, cyclophosphamide, and taxane. This study assesses the association of HR deficiency status with response to standard neoadjuvant chemotherapy in TNBC or BRCA1/2 mutation-associated breast cancer.Tumor samples were retrospectively obtained from 45 TNBC patients and 2 BRCA1/2 mutant, hormone receptor-positive/HER2-negative breast cancer patients who received anthracycline- and/or taxane-based neoadjuvant chemotherapy at Stanford University or Cedars-Sinai Medical Centers. The HRD score and tumor BRCA1/2 mutation status were determined from baseline tumor biopsies. HR deficient tumors were those with a HRD score of ? 42 or a tumor BRCA1/2 mutation. Response was categorized by the residual cancer burden (RCB) index.HR deficient patients were more likely to achieve a pathologic complete response (pCR) compared with non-deficient patients (OR 13.06, CI 1.52-11.241, p�=�0.0028). Among BRCA1/2 mutation wild-type patients, HR deficient patients were more likely to achieve a pCR (OR 16, 95% CI 1.65-160.41, p�=�0.0041) compared with HR non-deficient patients. Further, HRD scores were highly concordant pre- and post-therapy (Spearman correlation�>�99%).HR deficiency status is significantly associated with response to standard neoadjuvant chemotherapy in TNBC. This observation is consistent with the mechanisms of action of doxorubicin and cyclophosphamide as DNA damaging agents.

View details for PubMedID 29275435
Outstanding Questions in the Clinical Management of Triple-Negative Breast Cancer. Journal of oncology practice Gruber, J. J., Telli, M. L. 2017; 13 (5): 305-307
View details for DOI 10.1200/JOP.2017.023341

View details for PubMedID 28489983
NCCN Guidelines Insights: Breast Cancer, Version 1.2017. Journal of the National Comprehensive Cancer Network Gradishar, W. J., Anderson, B. O., Balassanian, R., Blair, S. L., Burstein, H. J., Cyr, A., Elias, A. D., Farrar, W. B., Forero, A., Giordano, S. H., Goetz, M. P., Goldstein, L. J., Isakoff, S. J., Lyons, J., Marcom, P. K., Mayer, I. A., McCormick, B., Moran, M. S., O'Regan, R. M., Patel, S. A., Pierce, L. J., Reed, E. C., Salerno, K. E., Schwartzberg, L. S., Sitapati, A., Smith, K. L., Smith, M. L., Soliman, H., Somlo, G., Telli, M., Ward, J. H., Shead, D. A., Kumar, R. 2017; 15 (4): 433-451
Abstract

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor-positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

View details for PubMedID 28404755
Exploiting Homologous Recombination Deficiency in TNBC CURRENT BREAST CANCER REPORTS Aleshin, A., Telli, M. L. 2017; 9 (1): 52?59
View details for DOI 10.1007/s12609-017-0236-9

View details for Web of Science ID 000397573800006
Reply to L. Del Mastro and A. Prat. Journal of clinical oncology Denduluri, N., Somerfield, M. R., Eisen, A., Holloway, J. N., Hurria, A., King, T. A., Lyman, G. H., Partridge, A. H., Telli, M. L., Trudeau, M. E., Wolff, A. C. 2017: JCO2016709758-?
View details for DOI 10.1200/JCO.2016.70.9758

View details for PubMedID 28095161
Interferon-beta represses cancer stem cell properties in triple-negative breast cancer. Proceedings of the National Academy of Sciences of the United States of America Doherty, M. R., Cheon, H., Junk, D. J., Vinayak, S., Varadan, V., Telli, M. L., Ford, J. M., Stark, G. R., Jackson, M. W. 2017; 114 (52): 13792?97
Abstract

Triple-negative breast cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed IFN/signal transducer and activator of transcription (IFN/STAT) gene signature and are often enriched for cancer stem cells (CSCs). We have found that human mammary epithelial cells that undergo an epithelial-to-mesenchymal transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with IFN-beta (IFN-?) led to a less aggressive epithelial/non-CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and reexpression of CD24 (a surface marker for non-CSCs), concomitant with an epithelium-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFN-?, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-? metagene signature correlates with improved patient survival, an immune response linked with tumor-infiltrating lymphocytes (TILs), and a repressed CSC metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3 and that treatment with IFN-? reduces CSC properties, suggesting a therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.

View details for PubMedID 29229854
Veliparib With Temozolomide or Carboplatin/Paclitaxel Versus Placebo With Carboplatin/Paclitaxel in Patients With BRCA1/2 Locally Recurrent/Metastatic Breast Cancer: Randomized Phase II Study. Annals of oncology : official journal of the European Society for Medical Oncology Han, H. S., Di�ras, V., Robson, M., Pal�cov�, M., Marcom, P. K., Jager, A., Bondarenko, I., Citrin, D., Campone, M., Telli, M. L., Domchek, S. M., Friedlander, M., Kaufman, B., Garber, J. E., Shparyk, Y., Chmielowska, E., Jakobsen, E. H., Kaklamani, V., Gradishar, W., Ratajczak, C. K., Nickner, C., Qin, Q., Qian, J., Shepherd, S. P., Isakoff, S. J., Puhalla, S. 2017
Abstract

Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, which interfere with DNA damage repair. Veliparib, a potent PARP inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer.Eligible patients ?18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1:1:1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and overall response rate (ORR).Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively (hazard ratio [HR], 0.789; 95% CI, 0.536-1.162; P=0.227), interim median OS 28.3 and 25.9 months (HR, 0.750; 95% CI, 0.503-1.117; P?=?0.156), and ORR 77.8% and 61.3% (P?=?0.027). For VT (versus PCP), median PFS was 7.4 months (HR, 1.858; 95% CI, 1.278-2.702; P=0.001), interim median OS 19.1 months (HR, 1.483; 95% CI, 1.032-2.131; P=0.032), and ORR 28.6% (P<0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP.Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared to PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information: NCT01506609.

View details for PubMedID 29045554
Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Non-amplified Metastatic Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Ma, C. X., Bose, R., Gao, F., Freedman, R. A., Telli, M. L., Kimmick, G., Winer, E. P., Naughton, M. J., Goetz, M. P., Russell, C., Tripathy, D., Cobleigh, M., Forero, A., Pluard, T. J., Anders, C. K., Niravath, P., Thomas, S., Anderson, J., Bumb, C., Banks, K. C., Lanman, R. B., Bryce, R., Lalani, A. S., Pfeifer, J. D., Hayes, D. F., Pegram, M. D., Blackwell, K., Bedard, P. L., Al-Kateb, H., Ellis, M. J. 2017
Abstract

Based on promising preclinical data, we conducted a single arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined �as complete/partial response (CR/PR) or stable disease (SD) ?24 weeks, in HER2(mut) non-amplified metastatic breast cancer (MBC).� Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2(mut) detection.�
Experimental Methods: �Tumor tissue positive for HER2(mut) was required for eligibility.� Neratinib was administered 240mg daily with prophylactic loperamide.� ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2(mut)).�

Results: �2.4% (9/381) tumors sequenced centrally harbored HER2(mut) (lobular 7.8% vs ductal 1.6%; p=0.026).� Thirteen additional HER2(mut) cases were identified locally.� 21 of these 22 HER2(mut) cases were estrogen receptor positive.� Sixteen patients (median age 58 [31-74] years and 3 [2-10] prior metastatic regimens) received neratinib.� The CBR was 31% (90%CI 13-55%), including 1 CR, 1 PR and 3 SD ?24 weeks).� Median PFS was 16 (90%CI: 8-31) weeks. Diarrhea (grade 2 44%, grade 3 25%) was the most common adverse event.� Baseline ctDNA sequencing identified the same HER2(mut) in 11 of 14 tumor positive cases (sensitivity 79%, 90%CI: 53-94%) and correctly assigned 32 of 32 informative negative cases (specificity 100%, 90%CI: 91-100%).� Additionally ctDNA HER2(mut) variant allele frequency decreased in 9 of 11 paired samples at week four, followed by an increase upon progression.
Conclusions:�Neratinib is active in HER2(mut), non-amplified MBC.� ctDNA sequencing offers a non-invasive strategy to identify patients with HER2(mut) cancers for clinical trial participation.

View details for PubMedID 28679771
A randomized Phase II study of veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in BRCA1/2 metastatic breast cancer: design and rationale. Future oncology Isakoff, S. J., Puhalla, S., Domchek, S. M., Friedlander, M., Kaufman, B., Robson, M., Telli, M. L., Di�ras, V., Han, H. S., Garber, J. E., Johnson, E. F., Maag, D., Qin, Q., Giranda, V. L., Shepherd, S. P. 2016: -?
Abstract

Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609).

View details for PubMedID 27739325
Lymph Node Ratio Analysis After Neoadjuvant Chemotherapy is Prognostic in Hormone Receptor-Positive and Triple-Negative Breast Cancer. Annals of surgical oncology Tsai, J., Bertoni, D., Hernandez-Boussard, T., Telli, M. L., Wapnir, I. L. 2016; 23 (10): 3310-3316
Abstract

Lymph node ratios (LNR), the proportion of positive lymph nodes over the number excised, both defined as ranges and single ratio values are prognostic of outcome. Little is known of the prognostic value of LNR after neoadjuvant chemotherapy (NAC) according to molecular subtype.From 2003 to 2014, patients who underwent definitive surgery after NAC were identified. LNR was calculated for node-positive patients who received axillary dissection or had at least 6 nodes removed. DFS was calculated using the Kaplan-Meier log rank test for yp N0-3 status, LNR categories (LNRC) ?0.20 (low), 0.21-0.65 (intermediate), >0.65 (high), and single LNR values.Of 428 NAC recipients, 263 were node negative and 165 (38.6�%) node positive: ypN1�=�97 (58.8�%), ypN2�=�43 (26.1�%), and ypN3�=�25 (15.2�%). Among node-positive cancers, the median number of LN removed was 14 (range, 6-51) and the median LNR was 0.22 (range, 0.03-1.0). Nodal stage was inversely associated with 5-year DFS: 91.5�% (ypN0), 74.5�% (ypN1), 49.8�% (ypN2), and 50.7�% (ypN3) (p�<�0.001). LNRC was similarly inversely associated with DFS: 69.1�% (low), 71.4�% (intermediate), 49.3�% (high) (p�<�0.001). Significant associations between LNRC and DFS were demonstrated in hormone receptor (HR)-positive and triple negative breast cancer (TNBC) subtypes, p�=�0.02 and p�=�0.003. A single-value LNR�?�0.15 in node-positive, HR-positive (94.1 vs 67.7�%; p�=�0.04) and TNBC (94.1 vs 47.8�%; p�=�0.001) groups was also significant.Residual nodal disease after NAC, analyzed by LNRC or LNR�=�0.15 cutoff value, is prognostic and can discriminate between favorable and unfavorable outcomes for HR-positive and TNBC cancers.

View details for DOI 10.1245/s10434-016-5319-8

View details for PubMedID 27401442
Acute, Unilateral Breast Toxicity From Gemcitabine in the Setting of Thoracic Inlet Obstruction. Journal of oncology practice / American Society of Clinical Oncology Weiskopf, K., Creighton, D., Lew, T., Caswell, J. L., Ouyang, D., Shah, A. T., Hofmann, L. V., Neal, J. W., Telli, M. L. 2016; 12 (8): 763-764
View details for DOI 10.1200/JOP.2016.014241

View details for PubMedID 27511721
Selection of Optimal Adjuvant Chemotherapy Regimens for Human Epidermal Growth Factor Receptor 2 (HER2) -Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline JOURNAL OF CLINICAL ONCOLOGY Denduluri, N., Somerfield, M. R., Eisen, A., Holloway, J. N., Hurria, A., King, T. A., Lyman, G. H., Partridge, A. H., Telli, M. L., Trudeau, M. E., Wolff, A. C. 2016; 34 (20): 2416-U186
Abstract

A Cancer Care Ontario (CCO) guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer including adjuvant targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancers was identified for adaptation.The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for adapting clinical practice guidelines developed by other organizations. The CCO guideline was reviewed for developmental rigor and content applicability.On the basis of the content review of the CCO guideline, the ASCO Panel agreed that, in general, the recommendations were clear and thorough and were based on the most relevant scientific evidence, and they presented options that will be acceptable to patients. However, for some topics addressed in the CCO guideline, the ASCO Panel formulated a set of adapted recommendations on the basis of local context and practice beliefs of the Panel members.Decisions regarding adjuvant chemotherapy regimens should take into account baseline recurrence risk, toxicities, likelihood of benefit, and host factors such as comorbidities. In high-risk HER2-negative populations with excellent performance status, anthracycline- and taxane-containing regimens are the standard of care. Docetaxel and cyclophosphamide for four cycles is an acceptable non-anthracycline regimen. In high-risk HER2-positive disease, sequential anthracycline and taxanes administered concurrently with trastuzumab or docetaxel, carboplatin, and trastuzumab for six cycles are recommended. An alternative regimen in a lower-risk, node-negative, HER2-positive population is paclitaxel and trastuzumab once per week for 12 cycles. Trastuzumab should be given for 1 year. Platinum salts should not be routinely administered in the adjuvant triple-negative population until survival efficacy data become available.

View details for DOI 10.1200/JCO.2016.67.0182

View details for Web of Science ID 000379127400013

View details for PubMedID 27091714
Invasive Breast Cancer Version 1.2016 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Gradishar, W. J., Anderson, B. O., Balassanian, R., Blair, S. L., Burstein, H. J., Cyr, A., Elias, A. D., Farrar, W. B., Forero, A., Giordano, S. H., Goetz, M., Goldstein, L. J., Hudis, C. A., Isakoff, S. J., Marcom, P. K., Mayer, I. A., McCormick, B., Moran, M., Patel, S. A., Pierce, L. J., Reed, E. C., Salerno, K. E., Schwartzberg, L. S., Smith, K. L., Smith, M. L., Soliman, H., Somlo, G., Telli, M., Ward, J. H., Shead, D. A., Kumar, R. 2016; 14 (3): 324-354
Abstract

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This article outlines the NCCN Guidelines specific to breast cancer that is locoregional (restricted to one region of the body), and discusses the management of clinical stage I, II, and IIIA (T3N1M0) tumors. For NCCN Guidelines on systemic adjuvant therapy after locoregional management of clinical stage I, II and IIIA (T3N1M0) and for management for other clinical stages of breast cancer, see the complete version of these guidelines at NCCN.org.

View details for Web of Science ID 000371997900012

View details for PubMedID 26957618
Breast Cancer After Hodgkin Lymphoma: The Price of Success. Oncology (Williston Park, N.Y.) Manzo, V., Dirbas, F., Telli, M. L. 2016; 30 (12)
View details for PubMedID 27987199
Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers CANCER DISCOVERY Watkins, J., Weekes, D., Shah, V., Gazinska, P., Joshi, S., Sidhu, B., Gillett, C., Pinder, S., Vanoli, F., Jasin, M., Mayrhofer, M., Isaksson, A., Cheang, M. C., Mirza, H., Frankum, J., Lord, C. J., Ashworth, A., Vinayak, S., Ford, J. M., Telli, M. L., Grigoriadis, A., Tutt, A. N. 2015; 5 (5): 488-505
Abstract

Triple-negative breast cancers (TNBCs) are characterised by a wide spectrum of genomic alterations, some of which might be caused by defects in DNA repair processes such as homologous recombination (HR). Despite this understanding, associating particular patterns of genomic instability with response to therapy has been challenging. Here, we show that Allelic-imbalanced Copy Number Aberrations (AiCNA) are more prevalent in TNBCs that respond to platinum-based chemotherapy, thus providing a candidate predictive biomarker for this disease. Furthermore, we show that a high level of AiCNA is linked with elevated expression of a meiosis-associated gene HORMAD1. Elevated HORMAD1 expression suppresses RAD51-dependent HR and drives the use of alternative forms of DNA repair, the generation of AiCNAs as well as sensitising cancer cells to HR targeting therapies. Our data therefore provides a mechanistic association between HORMAD1 expression, a specific pattern of genomic instability and an association with response to platinum-based chemotherapy in TNBC.

View details for DOI 10.1158/2159-8290.CD-14-1092

View details for PubMedID 25770156
Evolving treatment strategies for triple-negative breast cancer. Journal of the National Comprehensive Cancer Network Telli, M. 2015; 13 (5): 652-654
Abstract

Although not yet practice changing in early-stage triple-negative breast cancer, growing evidence suggests that neoadjuvant platinum-based therapy is active and that some patients may benefit from such an approach. Recent randomized phase III data suggests that carboplatin has comparable efficacy to docetaxel as first-line therapy in unselected advanced triple-negative breast cancer. In both settings, the efficacy of such treatment appears to be influenced by BRCA1/2 mutation status, with carriers of these mutations experiencing higher response rates. To optimize patient selection, biomarkers of response need to be incorporated into randomized clinical trials and validated. In addition to BRCA1/2, it is likely that measures of genomic instability and other germline biomarkers beyond BRCA1/2 may be associated with therapeutic sensitivity.

View details for PubMedID 25995421
Breast Cancer Version 2.2015 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Gradishar, W. J., Anderson, B. O., Balassanian, R., Blair, S. L., Burstein, H. J., Cyr, A., Elias, A. D., Farrar, W. B., Forero, A., Giordano, S. H., Goetz, M., Goldstein, L. J., Hudis, C. A., Isakoff, S. J., Marcom, P. K., Mayer, I. A., McCormick, B., Moran, M., Patel, S. A., Pierce, L. J., Reed, E. C., Salerno, K. E., Schwartzberg, L. S., Smith, K. L., Smith, M. L., Soliman, H., Somlo, G., Telli, M., Ward, J. H., Shead, D. A., Kumar, R. 2015; 13 (4): 448-475
Abstract

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This portion of the NCCN Guidelines discusses recommendations specific to the locoregional management of clinical stage I, II, and IIIA (T3N1M0) tumors.

View details for Web of Science ID 000352962200010

View details for PubMedID 25870381
The future of breast cancer systemic therapy: the next 10�years. Journal of molecular medicine (Berlin, Germany) Telli, M. L., Sledge, G. W. 2015; 93 (2): 119-125
Abstract

Over the past 50�years, substantial progress has been made in the systemic treatment of early-stage and advanced breast cancer. The use of chemotherapy in the adjuvant and metastatic settings has demonstrated proven efficacy and it has been clearly demonstrated that targeting the estrogen receptor and human growth factor receptor 2 (HER2) is efficacious in early and advanced disease. Despite these advances, vexing clinical challenges remain particularly related to the treatment of triple-negative breast cancer (TNBC; estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative) where little progress has been made therapeutically in more than a decade. While recurrences of hormone-responsive breast cancer are overall less common, late relapses after cessation of endocrine therapy are a more frequent occurrence in modern times and reflect the problem of underlying tumor dormancy that as yet has not been overcome. Multiple molecular tools are now available to interrogate the biology of breast cancer, though exactly how to make this information meaningful in the clinic has proven challenging, and molecularly driven clinical trials have faced feasibility challenges. In parallel, focus has expanded from tumor to host with the ability to ascertain underlying germline alterations, such as inherited BRCA1 and BRCA2 mutations, which may be responsible for breast cancer carcinogenesis and, importantly, may have implications for treatment. These clinical advances in germline genetics, made possible by both scientific investigation as well as the courts, still face challenges related to increasing encounters with variants of unknown significance and difficulty in predicting risks associated with less well-characterized inherited cancer predisposition syndromes. In this paper, we attempt to predict the next 10�years of breast cancer, in particular focusing on how the past serves as prologue to the future in this disease.

View details for DOI 10.1007/s00109-014-1238-y

View details for PubMedID 25566982
Breast Cancer, Version 1.2016. Journal of the National Comprehensive Cancer Network : JNCCN Gradishar, W. J., Anderson, B. O., Balassanian, R., Blair, S. L., Burstein, H. J., Cyr, A., Elias, A. D., Farrar, W. B., Forero, A., Giordano, S. H., Goetz, M., Goldstein, L. J., Hudis, C. A., Isakoff, S. J., Marcom, P. K., Mayer, I. A., McCormick, B., Moran, M., Patel, S. A., Pierce, L. J., Reed, E. C., Salerno, K. E., Schwartzberg, L. S., Smith, K. L., Smith, M. L., Soliman, H., Somlo, G., Telli, M., Ward, J. H., Shead, D. A., Kumar, R. 2015; 13 (12): 1475?85
Abstract

These NCCN Guideline Insights highlight the important updates to the systemic therapy recommendations in the 2016 NCCN Guidelines for Breast Cancer. In the most recent version of these guidelines, the NCCN Breast Cancer Panel included a new section on the principles of preoperative systemic therapy. In addition, based on new evidence, the panel updated systemic therapy recommendations for women with hormone receptor-positive breast cancer in the adjuvant and metastatic disease settings and for patients with HER2-positive metastatic breast cancer. This report summarizes these recent updates and discusses the rationale behind them.

View details for PubMedID 26656517
(18)F-FPPRGD2 PET/CT: pilot phase evaluation of breast cancer patients. Radiology Iagaru, A., Mosci, C., Shen, B., Chin, F. T., Mittra, E., Telli, M. L., Gambhir, S. S. 2014; 273 (2): 549-559
Abstract

Purpose To present data from the first prospective pilot phase trial of breast cancer participants imaged with fluorine 18 ((18)F)-2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid (RGD) peptide (PEG3-E[c{RGDyk}]2) (FPPRGD2), a radiopharmaceutical agent used in positron emission tomographic (PET) imaging. Materials and Methods The local institutional review board approved the HIPAA-compliant protocol. Written informed consent was obtained from each patient. Eight women (age range, 44-67 years; mean age, 54.3 years � 8.8 [standard deviation]) with newly diagnosed or recurrent breast cancer were recruited between November 2010 and February 2011. (18)F-FPPRGD2 PET/computed tomographic (CT) and (18)F-fluorodeoxyglucose (FDG) PET/CT examinations were performed within 3 weeks of each other. Dynamic (18)F-FPPRGD2 PET and two whole-body static (18)F-FPPRGD2 PET/CT scans were obtained. During this time, vital signs and electrocardiograms were recorded at regular intervals. Blood samples were obtained before the injection of (18)F-FPPRGD2 and at 24 hours and 1 week after injection to evaluate for toxicity. A nonparametric version of multivariate analysis of variance was used to assess the safety outcome measures simultaneously across time points. A paired two-sample t test was performed to compare the maximum standardized uptake values (SUVmax). Results (18)F-FPPRGD2 was well tolerated, without noticeable changes in vital signs, on electrocardiograms, or in laboratory values. A total of 30 lesions were evaluated at (18)F-FDG PET/CT and (18)F-FPPRGD2 PET/CT. The primary breast lesions had (18)F-FPPRGD2 uptake with SUVmax of 2.4-9.4 (mean, 5.6 � 2.8) 60 minutes after injection, compared with (18)F-FDG uptake with SUVmax of 2.8-18.6 (mean, 10.4 � 7.2). Metastatic lesions also showed (18)F-FPPRGD2 uptake, with SUVmax of 2.4-9.7 (mean, 5.0 � 2.3) at 60 minutes, compared with (18)F-FDG uptake with SUVmax of 2.2-14.6 (mean, 6.6 � 4.2). Conclusion Data from this pilot phase study suggest that (18)F-FPPRGD2 is a safe PET radiopharmaceutical agent. Evaluation of (18)F-FPPRGD2 in participants with breast cancer demonstrated significant uptake in the primary lesion and in the metastases. Larger cohorts are required to confirm these preliminary findings. � RSNA, 2014.

View details for DOI 10.1148/radiol.14140028

View details for PubMedID 25033190
Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition. Breast cancer research Zhang, H., Cohen, A. L., Krishnakumar, S., Wapnir, I. L., Veeriah, S., Deng, G., Coram, M. A., Piskun, C. M., Longacre, T. A., Herrler, M., Frimannsson, D. O., Telli, M. L., Dirbas, F. M., Matin, A. C., Dairkee, S. H., Larijani, B., Glinsky, G. V., Bild, A. H., Jeffrey, S. S. 2014; 16 (2): R36-?
Abstract

Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies. Phosphatidylinositide 3-kinase (PI3K) / mammalian target of rapamycin (mTOR) pathways are frequently activated in TNBC patient tumors at the genome, gene expression and protein levels, and mTOR inhibitors have been shown to inhibit growth in TNBC cell lines. We describe a panel of patient-derived xenografts representing multiple TNBC subtypes and use them to test preclinical drug efficacy of two mTOR inhibitors, sirolimus (rapamycin) and temsirolimus (CCI-779).We generated a panel of seven patient-derived orthotopic xenografts from six primary TNBC tumors and one metastasis. Patient tumors and corresponding xenografts were compared by histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) sequencing; TNBC subtypes were determined. Using a previously published logistic regression approach, we generated a rapamycin response signature from Connectivity Map gene expression data and used it to predict rapamycin sensitivity in 1401 human breast cancers of different intrinsic subtypes, prompting in vivo testing of mTOR inhibitors and doxorubicin in our TNBC xenografts.Patient-derived xenografts recapitulated histology, biomarker expression and global genomic features of patient tumors. Two primary tumors had PIK3CA coding mutations, and 5/6 primary tumors showed flanking intron single nucleotide polymorphisms (SNPs) with conservation of sequence variations between primary tumors and xenografts, even on subsequent xenograft passages. Gene expression profiling showed that our models represent at least four of six TNBC subtypes. The rapamycin response signature predicted sensitivity for 94% of basal-like breast cancers in a large dataset. Drug testing of mTOR inhibitors in our xenografts showed 77 to 99% growth inhibition, significantly more than doxorubicin; protein phosphorylation studies indicated constitutive activation of the mTOR pathway that decreased with treatment. However, no tumor was completely eradicated.A panel of patient-derived xenograft models covering a spectrum of TNBC subtypes was generated that histologically and genomically matched original patient tumors. Consistent with in silico predictions, mTOR inhibitor testing in our TNBC xenografts showed significant tumor growth inhibition in all, suggesting that mTOR inhibitors can be effective in TNBC, but will require use with additional therapies, warranting investigation of optimal drug combinations.

View details for DOI 10.1186/bcr3640

View details for PubMedID 24708766
The role of platinum therapy in triple-negative breast cancer Breast Cancer Management Afghahi, A., Telli, M. L. 2014; 3 (4): 377-385
View details for DOI 10.2217/bmt.14.21
Optimizing chemotherapy in triple-negative breast cancer: the role of platinum. American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting Telli, M. 2014; 34: e37-42
Abstract

Although characterization of triple-negative breast cancer (TNBC) using mRNA gene expression profiling has certainly provided important insights, the concept of targeting DNA repair defects with DNA damaging therapeutics such as platinum in TNBC has been advanced from studies focusing on both germline and somatic genetic alterations associated with this breast cancer subtype. A growing body of preclinical and clinical data suggests that platinum chemotherapy has a potential role to play in the treatment of both early-stage and advanced TNBC, though results are not yet definitive. Randomized clinical trials that incorporate biomarkers of response, including germline BRCA1 and BRCA2 mutation status as well as tumor-based measures of genomic "scarring" resulting from the accumulation of DNA damage in tumors with deficient repair capacity, will help to clarify the optimal use and activity of platinum in TNBC.

View details for DOI 10.14694/EdBook_AM.2014.34.e37

View details for PubMedID 24857126
Single cell mutational analysis of PIK3CA in circulating tumor cells and metastases in breast cancer reveals heterogeneity, discordance, and mutation persistence in cultured disseminated tumor cells from bone marrow. BMC cancer Deng, G., Krishnakumar, S., Powell, A. A., Zhang, H., Mindrinos, M. N., Telli, M. L., Davis, R. W., Jeffrey, S. S. 2014; 14: 456-?
Abstract

Therapeutic decisions in cancer are generally guided by molecular biomarkers or, for some newer therapeutics, primary tumor genotype. However, because biomarkers or genotypes may change as new metastases emerge, circulating tumor cells (CTCs) from blood are being investigated for a role in guiding real-time drug selection during disease progression, expecting that CTCs will comprehensively represent the full spectrum of genomic changes in metastases. However, information is limited regarding mutational heterogeneity among CTCs and metastases in breast cancer as discerned by single cell analysis. The presence of disseminated tumor cells (DTCs) in bone marrow also carry prognostic significance in breast cancer, but with variability between CTC and DTC detection. Here we analyze a series of single tumor cells, CTCs, and DTCs for PIK3CA mutations and report CTC and corresponding metastatic genotypes.We used the MagSweeper, an immunomagnetic separation device, to capture live single tumor cells from breast cancer patients' primary and metastatic tissues, blood, and bone marrow. Single cells were screened for known hotspot mutations in exons 9 and 20 of the PIK3CA gene. Captured DTCs grown in cell culture were also sequenced for PIK3CA mutations.Among 242 individual tumor cells isolated from 17 patients and tested for mutations, 48 mutated tumor cells were identified in three patients. Single cell analyses revealed mutational heterogeneity among CTCs and tumor cells in tissues. In a patient followed serially, there was mutational discordance between CTCs, DTCs, and metastases, and among CTCs isolated at different time points. DTCs from this patient propagated in vitro contained a PIK3CA mutation, which was maintained despite morphological changes during 21 days of cell culture.Single cell analysis of CTCs can demonstrate genotypic heterogeneity, changes over time, and discordance from DTCs and distant metastases. We present a cautionary case showing that CTCs from any single blood draw do not always reflect metastatic genotype, and that CTC and DTC analyses may provide independent clinical information. Isolated DTCs remain viable and can be propagated in culture while maintaining their original mutational status, potentially serving as a future resource for investigating new drug therapies.

View details for DOI 10.1186/1471-2407-14-456

View details for PubMedID 24947048
Dynamic contrast-enhanced MRI-based biomarkers of therapeutic response in triple-negative breast cancer. Journal of the American Medical Informatics Association Golden, D. I., Lipson, J. A., Telli, M. L., Ford, J. M., Rubin, D. L. 2013; 20 (6): 1059-1066
Abstract

To predict the response of breast cancer patients to neoadjuvant chemotherapy (NAC) using features derived from dynamic contrast-enhanced (DCE) MRI.60 patients with triple-negative early-stage breast cancer receiving NAC were evaluated. Features assessed included clinical data, patterns of tumor response to treatment determined by DCE-MRI, MRI breast imaging-reporting and data system descriptors, and quantitative lesion kinetic texture derived from the gray-level co-occurrence matrix (GLCM). All features except for patterns of response were derived before chemotherapy; GLCM features were determined before and after chemotherapy. Treatment response was defined by the presence of residual invasive tumor and/or positive lymph nodes after chemotherapy. Statistical modeling was performed using Lasso logistic regression.Pre-chemotherapy imaging features predicted all measures of response except for residual tumor. Feature sets varied in effectiveness at predicting different definitions of treatment response, but in general, pre-chemotherapy imaging features were able to predict pathological complete response with area under the curve (AUC)=0.68, residual lymph node metastases with AUC=0.84 and residual tumor with lymph node metastases with AUC=0.83. Imaging features assessed after chemotherapy yielded significantly improved model performance over those assessed before chemotherapy for predicting residual tumor, but no other outcomes.DCE-MRI features can be used to predict whether triple-negative breast cancer patients will respond to NAC. Models such as the ones presented could help to identify patients not likely to respond to treatment and to direct them towards alternative therapies.

View details for DOI 10.1136/amiajnl-2012-001460

View details for PubMedID 23785100
A clinical trial of lovastatin for modification of biomarkers associated with breast cancer risk BREAST CANCER RESEARCH AND TREATMENT Vinayak, S., Schwartz, E. J., Jensen, K., Lipson, J., Alli, B., McPherson, L., Fernandez, A. M., Sharma, V. B., Staton, A., Mills, M. A., Schackmann, E. A., Telli, M. L., Kardashian, A., Ford, J. M., Kurian, A. W. 2013; electronic publication ahead of print, October 30
Qualitative and quantitative image-based biomarkers of therapeutic response in triple-negative breast cancer. AMIA Summits on Translational Science proceedings AMIA Summit on Translational Science Golden, D. I., Lipson, J. A., Telli, M. L., Ford, J. M., Rubin, D. L. 2013; 2013: 62-?
Abstract

Experimental targeted treatments for neoadjuvant chemotherapy for triple-negative breast cancer are currently underway, and a current challenge is predicting which patients will respond to these therapies. In this study, we use data from dynamic contrast-enhanced MRI (DCE-MRI) images to predict whether patients with triple negative breast cancer will respond to an experimental neoadjuvant chemotherapy regimen. Using pre-therapy image-based features that are both qualitative (e.g., morphological BI-RADS categories) and quantitative (e.g., lesion texture), we built a model that was able to predict whether patients will have residual invasive cancer with lymph nodes metastases following therapy (receiver operating characteristic area under the curve of 0.83, sensitivity=0.73, specificity=0.83). This model's performance is at a level that is potentially clinically valuable for predicting which patients may or may not benefit from similar treatments in the future.

View details for PubMedID 24303300
Prevalence, putative mechanisms, and current management of sleep problems during chemotherapy for cancer. Nature and science of sleep Palesh, O., Peppone, L., Innominato, P. F., Janelsins, M., Jeong, M., Sprod, L., Savard, J., Rotatori, M., Kesler, S., Telli, M., Mustian, K. 2012; 4: 151-162
Abstract

Sleep problems are highly prevalent in cancer patients undergoing chemotherapy. This article reviews existing evidence on etiology, associated symptoms, and management of sleep problems associated with chemotherapy treatment during cancer. It also discusses limitations and methodological issues of current research. The existing literature suggests that subjectively and objectively measured sleep problems are the highest during the chemotherapy phase of cancer treatments. A possibly involved mechanism reviewed here includes the rise in the circulating proinflammatory cytokines and the associated disruption in circadian rhythm in the development and maintenance of sleep dysregulation in cancer patients during chemotherapy. Various approaches to the management of sleep problems during chemotherapy are discussed with behavioral intervention showing promise. Exercise, including yoga, also appear to be effective and safe at least for subclinical levels of sleep problems in cancer patients. Numerous challenges are associated with conducting research on sleep in cancer patients during chemotherapy treatments and they are discussed in this review. Dedicated intervention trials, methodologically sound and sufficiently powered, are needed to test current and novel treatments of sleep problems in cancer patients receiving chemotherapy. Optimal management of sleep problems in patients with cancer receiving treatment may improve not only the well-being of patients, but also their prognosis given the emerging experimental and clinical evidence suggesting that sleep disruption might adversely impact treatment and recovery from cancer.

View details for PubMedID 23486503
Chest Wall Leiomyosarcoma After Breast-Conservative Therapy for Early-Stage Breast Cancer in a Young Woman With Li-Fraumeni Syndrome JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Henry, E., Villalobos, V., Million, L., Jensen, K. C., West, R., Ganjoo, K., Lebensohn, A., Ford, J. M., Telli, M. L. 2012; 10 (8): 939-942
Abstract

Li-Fraumeni syndrome (LFS) is one of the most penetrant forms of familial cancer susceptibility syndromes, characterized by early age at tumor onset and a wide spectrum of malignant tumors. Identifying LFS in patients with cancer is clinically imperative because they have an increased sensitivity to ionizing radiation and are more likely to develop radiation-induced secondary malignancies. This case report describes a young woman whose initial presentation of LFS was early-onset breast cancer and whose treatment of this primary malignancy with breast conservation likely resulted in a secondary malignancy arising in her radiation field. As seen in this case, most breast cancers in patients with LFS exhibit a triple-positive phenotype (estrogen receptor-positive/progesterone receptor-positive/HER2-positive). Although this patient met classic LFS criteria based on age and personal and family history of cancer, the NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer endorse genetic screening for TP53 mutations in a subset of patients with early-onset breast cancer, even in the absence of a suggestive family history, because of the potential for de novo TP53 mutations.

View details for PubMedID 22878818
Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort BREAST CANCER RESEARCH AND TREATMENT Masciari, S., Dillon, D. A., Rath, M., Robson, M., Weitzel, J. N., Balmana, J., Gruber, S. B., Ford, J. M., Euhus, D., Lebensohn, A., Telli, M., Pochebit, S. M., Lypas, G., Garber, J. E. 2012; 133 (3): 1125-1130
Abstract

Breast cancer is the most common tumor in women with Li-Fraumeni Syndrome (LFS), an inherited cancer syndrome associated with germline mutations in the TP53 tumor suppressor gene. Their lifetime breast cancer risk is 49% by age 60. Breast cancers in TP53 mutation carriers recently have more often been reported to be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series. We seek to complement the existing small literature with this report of a histopathologic analysis of breast cancers from women with documented LFS. Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutation carriers were assembled from investigators in the LFS consortium. Central histology review was performed on 93% of the specimens by a single breast pathologist from a major university hospital. Histology, grade, and hormone receptor status were assessed by immunohistochemistry; HER-2 status was defined by immunohistochemistry and/or FISH. The 43 tumors from 39 women comprise 32 invasive ductal carcinomas and 11 ductal carcinomas in situ (DCIS). No other histologies were observed. The median age at diagnosis was 32�years (range 22-46). Of the invasive cancers, 84% were positive for ER and/or PR; and 81% were high grade. Sixty three percent of invasive and 73% of in situ carcinomas were positive for Her2/neu (IHC 3+ or FISH amplified). Of the invasive tumors, 53% were positive for both ER and HER2+; other ER/PR/HER2 combinations were observed. The DCIS were positive for ER and HER2 in 27% of the cases. This report of the phenotype of breast cancers from women with LFS nearly doubles the literature on this topic. Most DCIS and invasive ductal carcinomas in LFS are hormone receptor positive and/or HER-2 positive. These findings suggest that modern treatments may result in improved outcomes for women with LFS-associated breast cancer.

View details for DOI 10.1007/s10549-012-1993-9

View details for Web of Science ID 000305914900030

View details for PubMedID 22392042
Underestimating Cardiac Toxicity in Cancer Trials: Lessons Learned? JOURNAL OF CLINICAL ONCOLOGY Witteles, R. M., Telli, M. 2012; 30 (16): 1916-1918
View details for DOI 10.1200/JCO.2011.40.4012

View details for Web of Science ID 000304596800010

View details for PubMedID 22454419
Single Cell Profiling of Circulating Tumor Cells: Transcriptional Heterogeneity and Diversity from Breast Cancer Cell Lines PLOS ONE Powell, A. A., Talasaz, A. H., Zhang, H., Coram, M. A., Reddy, A., Deng, G., Telli, M. L., Advani, R. H., Carlson, R. W., Mollick, J. A., Sheth, S., Kurian, A. W., Ford, J. M., Stockdale, F. E., Quake, S. R., Pease, R. F., Mindrinos, M. N., Bhanot, G., Dairkee, S. H., Davis, R. W., Jeffrey, S. S. 2012; 7 (5)
Abstract

To improve cancer therapy, it is critical to target metastasizing cells. Circulating tumor cells (CTCs) are rare cells found in the blood of patients with solid tumors and may play a key role in cancer dissemination. Uncovering CTC phenotypes offers a potential avenue to inform treatment. However, CTC transcriptional profiling is limited by leukocyte contamination; an approach to surmount this problem is single cell analysis. Here we demonstrate feasibility of performing high dimensional single CTC profiling, providing early insight into CTC heterogeneity and allowing comparisons to breast cancer cell lines widely used for drug discovery.We purified CTCs using the MagSweeper, an immunomagnetic enrichment device that isolates live tumor cells from unfractionated blood. CTCs that met stringent criteria for further analysis were obtained from 70% (14/20) of primary and 70% (21/30) of metastatic breast cancer patients; none were captured from patients with non-epithelial cancer (n = 20) or healthy subjects (n = 25). Microfluidic-based single cell transcriptional profiling of 87 cancer-associated and reference genes showed heterogeneity among individual CTCs, separating them into two major subgroups, based on 31 highly expressed genes. In contrast, single cells from seven breast cancer cell lines were tightly clustered together by sample ID and ER status. CTC profiles were distinct from those of cancer cell lines, questioning the suitability of such lines for drug discovery efforts for late stage cancer therapy.For the first time, we directly measured high dimensional gene expression in individual CTCs without the common practice of pooling such cells. Elevated transcript levels of genes associated with metastasis NPTN, S100A4, S100A9, and with epithelial mesenchymal transition: VIM, TGF�1, ZEB2, FOXC1, CXCR4, were striking compared to cell lines. Our findings demonstrate that profiling CTCs on a cell-by-cell basis is possible and may facilitate the application of 'liquid biopsies' to better model drug discovery.

View details for DOI 10.1371/journal.pone.0033788

View details for PubMedID 22586443
Chemotherapy-Associated Cardiotoxicity: How Often Does it Really Occur and How Can it Be Prevented? HEART FAILURE CLINICS Witteles, R. M., Fowler, M. B., Telli, M. L. 2011; 7 (3): 333-?
Abstract

Cardiotoxicity remains the limiting factor for many forms of cancer therapy and is the focus of growing research and clinical emphasis. This article outlines the current clinical evidence for left ventricular dysfunction and heart failure for the two most important classes of cardiotoxic chemotherapeutic agents, examines the potential pitfalls that have led to underestimated rates of left ventricular dysfunction from these agents, and reviews strategies for screening for and providing prophylaxis against chemotherapy-associated left ventricular dysfunction.

View details for DOI 10.1016/j.hfc.2011.03.005

View details for PubMedID 21749885
Asian ethnicity and breast cancer subtypes: a study from the California Cancer Registry BREAST CANCER RESEARCH AND TREATMENT Telli, M. L., Chang, E. T., Kurian, A. W., Keegan, T. H., McClure, L. A., Lichtensztajn, D., Ford, J. M., Gomez, S. L. 2011; 127 (2): 471-478
Abstract

The distribution of breast cancer molecular subtypes has been shown to vary by race/ethnicity, highlighting the importance of host factors in breast tumor biology. We undertook the current analysis to determine population-based distributions of breast cancer subtypes among six ethnic Asian groups in California. We defined immunohistochemical (IHC) surrogates for each breast cancer subtype among Chinese, Japanese, Filipina, Korean, Vietnamese, and South Asian patients diagnosed with incident, primary, invasive breast cancer between 2002 and 2007 in the California Cancer Registry as: hormone receptor-positive (HR+)/HER2- [estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+), human epidermal growth factor receptor 2-negative (HER2-)], triple-negative (ER-, PR-, and HER2-), and HER2-positive (ER�, PR�, and HER2+). We calculated frequencies of breast cancer subtypes among Asian ethnic groups and evaluated their associations with clinical and demographic factors. Complete IHC data were available for 8,140 Asian women. Compared to non-Hispanic White women, Korean [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.5-2.2], Filipina (OR = 1.3, 95% CI = 1.2-1.5), Vietnamese (OR = 1.3, 95% CI = 1.1-1.6), and Chinese (OR = 1.1, 95% CI = 1.0-1.3) women had a significantly increased risk of being diagnosed with HER2-positive breast cancer subtypes after adjusting for age, stage, grade, socioeconomic status, histology, diagnosis year, nativity, and hospital ownership status. We report a significant ethnic disparity in HER2-positive breast cancer in a large population-based cohort enriched for Asian-Americans. Given the poor prognosis and high treatment costs of HER2-positive breast cancer, our results have implications for healthcare resource utilization, cancer biology, and clinical care.

View details for DOI 10.1007/s10549-010-1173-8

View details for PubMedID 20957431
Trastuzumab-Related Cardiac Dysfunction JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Telli, M. L., Witteles, R. M. 2011; 9 (2): 243-249
Abstract

The use of trastuzumab in the adjuvant and metastatic treatment of breast cancer is associated with both symptomatic and asymptomatic cardiotoxicity. The long-term significance of these events, isolating known cardiotoxic effects of anthracyclines from those of trastuzumab, and the appropriateness of referring to trastuzumab-related cardiotoxicity as reversible rather than responsive to trastuzumab withdrawal and heart failure medical therapy, are issues that continue to be debated. This article provides an overview of the available cardiac safety data from the major trastuzumab clinical trials in breast cancer, highlighting areas of ongoing controversy. Important recent data documenting the occurrence and prognostic use of cardiac troponin I elevations among patients treated with trastuzumab are placed into context with the mechanistic insight these data provide and the implications for clinical practice today.

View details for PubMedID 21310845
Left Ventricular Dysfunction in Patients Receiving Cardiotoxic Cancer Therapies Are Clinicians Responding Optimally? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Yoon, G. J., Telli, M. L., Kao, D. P., Matsuda, K. Y., Carlson, R. W., Witteles, R. M. 2010; 56 (20): 1644-1650
Abstract

The purpose of this study was to examine treatment practices for cancer therapy-associated decreased left ventricular ejection fraction (LVEF) detected on echocardiography and whether management was consistent with American College of Cardiology/American Heart Association guidelines.Patients treated with anthracyclines or trastuzumab are at risk of cardiotoxicity. Decreased LVEF represents a Class I indication for drug intervention according to American College of Cardiology/American Heart Association guidelines.Patients receiving anthracycline or trastuzumab at Stanford University from October 2005 to October 2007 and who had undergone echocardiography before and after receiving an anthracycline or trastuzumab were identified. Chart review examined chemotherapy regimens, cardiac risk factors, imaging results, concomitant medications, and cardiology consultations.Eighty-eight patients received therapy with an anthracycline or trastuzumab and had a pre-treatment and follow-up echocardiogram. Ninety-two percent were treated with anthracyclines, 17% with trastuzumab after an anthracycline, and 8% with trastuzumab without previous treatment with anthracycline. Mean baseline LVEF was 60%, with 14% having a baseline <55%. Forty percent had decreased LVEF (<55%) after anthracycline and/or trastuzumab treatment. Of these patients, 40% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 51% beta-blocker therapy, and 54% cardiology consultation. Of patients with asymptomatic decreased LVEF, 31% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 35% beta-blocker therapy, and 42% cardiology consultation. Of those with symptomatic decreased LVEF, 67% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 100% beta-blocker therapy, and 89% cardiology consultation.Many cancer survivors are not receiving treatment consistent with heart failure guidelines. There is substantial opportunity for collaboration between oncologists and cardiologists to improve the care of oncology patients receiving cardiotoxic therapy.

View details for DOI 10.1016/j.jacc.2010.07.023

View details for PubMedID 21050974
PARP inhibitors in breast cancer. Clinical advances in hematology & oncology : H&O Telli, M. L., Ford, J. M. 2010; 8 (9): 629-635
Abstract

The therapeutic implications of DNA damage in cancer therapy have long been appreciated and form the basis of many successful cytotoxic chemotherapy and radiotherapy treatment strategies. A novel class of DNA repair defect targeted therapeutics that inhibit poly (ADP-Ribose) polymerase (PARP) are being rapidly developed in breast cancer based on exciting preliminary clinical activity as single agents in BRCA mutation-associated breast cancer and in combination with chemotherapy in triple-negative breast cancer. Though there is widespread enthusiasm to move these drugs forward quickly, much remains to be understood about the optimal use of the novel agents. Here we review the clinical development of PARP inhibitors in breast cancer and highlight clinical trials in progress. We also provide commentary on a series of outstanding questions in the field, the answers to which will be critical for the successful development of PARP inhibitor-based strategies in early- and late-stage breast cancer.

View details for PubMedID 21157412
Novel Treatment Approaches for Triple-Negative Breast Cancer CLINICAL BREAST CANCER Telli, M. L., Ford, J. M. 2010; 10: E16-E22
Abstract

Triple-negative breast cancers share an aggressive biology, marked by increased recurrence risk and poorer survival compared with hormone receptor-positive subtypes. Few therapeutic trials have specifically focused on triple-negative breast cancer, and the treatment of patients with early-stage triple-negative breast cancer has changed little in the past decade. Over this time, however, attention has shifted to treatment approaches based on molecular subtypes of breast cancer, and investigation into the mechanistic underpinnings of these distinct subtypes has exploded. Converging preclinical rationales combined with early provocative clinical efficacy has focused recent attention on strategies targeting DNA repair defects for the treatment of patients with triple-negative and BRCA mutation-associated breast cancers. These developments are very promising and suggest that major advances in the targeted treatment of patients with triple-negative breast cancer are in sight. This review provides an overview of the clinical features of triple-negative breast cancer and current treatment strategies in the adjuvant setting. Mechanisms of DNA repair and the DNA damage response are reviewed to provide background for understanding novel approaches targeting DNA repair defects in this disease with DNA-damaging chemotherapeutic agents and poly(ADP-ribose) polymerase inhibitors. Ongoing studies, including those investigating the role of antiangiogenic therapies, are also reviewed.

View details for DOI 10.3816/CBC.2010.s.003

View details for PubMedID 20587403
Increasing Mastectomy Rates for Early-Stage Breast Cancer? Population-Based Trends From California JOURNAL OF CLINICAL ONCOLOGY Gomez, S. L., Lichtensztajn, D., Kurian, A. W., Telli, M. L., Chang, E. T., Keegan, T. H., Glaser, S. L., Clarke, C. A. 2010; 28 (10): E155-E157
View details for DOI 10.1200/JCO.2009.26.1032

View details for Web of Science ID 000276152200036

View details for PubMedID 20159812
Longer Relative Telomere Length in Blood from Women with Sporadic and Familial Breast Cancer Compared with Healthy Controls CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gramatges, M. M., Telli, M. L., Balise, R., Ford, J. M. 2010; 19 (2): 605-613
Abstract

Telomeres cap the ends of chromosomes and are composed of a series of noncoding hexamer repeats. Telomeres protect the integrity of DNA coding sequences and are integral to the maintenance of genomic stability. Previous studies have shown an association between shortened lymphocyte telomeres and increased risk for specific cancers. However, the association between telomere length and breast cancer risk is less clear. We examined the relative telomere length (RTL) in blood from women with no personal or family history of cancer (controls) compared with different populations of women with breast cancer and women at high genetic risk for developing breast cancer. RTL was determined as the telomere to single gene copy number ratio assessed by quantitative PCR. Breast cancer cases (low risk, n = 40; high risk, n = 62) had significantly longer RTL compared with unaffected controls (n = 50; mean RTL = 1.11 versus 0.84; P < 0.0001). The assessment of risk by RTL quartile showed an increased risk for breast cancer with each longer quartile, with the most significant risk observed in the longest quartile (odds ratio, 23.3; confidence interval, 4.4-122.3; P < 0.0003). Women without breast cancer but at high risk due to family history (n = 30) also showed longer telomeres than controls (mean RTL = 1.09 versus 0.84; P < 0.0001). Our analysis supports previous findings of longer RTL in breast cancer cases compared with controls, and is the first to observe longer RTL in women without breast cancer identified as high risk based on family history.

View details for DOI 10.1158/1055-9965.EPI-09-0896

View details for Web of Science ID 000278403900035

View details for PubMedID 20142254
First-Line Chemotherapy for Metastatic Breast Cancer CLINICAL BREAST CANCER Telli, M. L., Carlson, R. W. 2009; 9: S66-S72
Abstract

The selection of first-line chemotherapy for metastatic breast cancer (MBC) is complex because of the myriad of treatment options available and the inherent biologic heterogeneity of the disease. The potential treatment options are greatly influenced by estrogen and progesterone receptor and HER2 status of the tumor, and biopsy with reassessment of these markers at the time of disease recurrence is strongly recommended. Metastatic breast cancer is generally an incurable disease, with survival that could range from months to several years. Important but modest improvements in overall survival (OS) have been observed for women with MBC over the past few decades, in part because of improvements in systemic therapy. For women with endocrine-responsive disease, hormonal therapy is the appropriate initial treatment choice at the time of disease recurrence with rare exception. Initiation of systemic chemotherapy is appropriate for women with disease that is either hormone receptor negative, endocrine therapy refractory, or rapidly progressive with visceral involvement. The addition of trastuzumab to chemotherapy for women with HER2-positive breast cancer represents a clear standard of care. For HER2-negative MBC, sequential single-agent chemotherapy is preferred over combination therapy as a result of the more favorable toxicity profile and absence of a clinically significant improvement in survival with combination treatment. Many single-agent chemotherapeutic agents have activity in MBC, with most data supporting an anthracycline- or taxane-based approach. Bevacizumab in combination with chemotherapy prolongs progression-free survival in women with MBC, though its position in the first-line treatment of MBC relative to standard chemotherapy remains unclear at this time because of lack of OS benefit.

View details for DOI 10.3816/CBC.2009.s.007

View details for Web of Science ID 000267527100003

View details for PubMedID 19596645
Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate ANNALS OF ONCOLOGY Telli, M. L., Witteles, R. M., Fisher, G. A., Srinivas, S. 2008; 19 (9): 1613-1618
Abstract

In the pivotal phase III metastatic renal cell carcinoma trial, updated data indicates that 21% of sunitinib-treated patients experienced a decline in left ventricular ejection fraction to below normal. This cardiotoxicity was reported to be reversible and without clinical sequelae. We conducted a retrospective analysis of our institutional experience of cardiotoxicity with sunitinib after observing a high incidence of symptomatic heart failure.Patients receiving sunitinib at Stanford University from 1 July 2004 to 1 July 2007 were identified. Medical records were reviewed and those patients experiencing symptomatic grade 3/4 left ventricular systolic dysfunction were identified. Potential cardiac risk factors were analyzed.Forty-eight patients treated with sunitinib were assessable. Seven patients experienced symptomatic grade 3/4 left ventricular dysfunction 22-435 days after initiation of sunitinib. Three patients had persistent cardiac dysfunction after discontinuation of sunitinib and initiation of heart failure therapy. A history of congestive heart failure, coronary artery disease and lower body mass index were factors associated with increased risk.Among patients treated with sunitinib at our institution, 15% developed symptomatic grade 3/4 heart failure. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand.

View details for DOI 10.1093/annonc/mdn168

View details for Web of Science ID 000259505400015

View details for PubMedID 18436521
Trastuzumab-related cardiotoxicity: Calling into question the concept of reversibility JOURNAL OF CLINICAL ONCOLOGY Telli, M. L., Hunt, S. A., Carlson, R. W., Guardino, A. E. 2007; 25 (23): 3525-3533
Abstract

To assess the spectrum and reversibility of the cardiotoxicity observed in the adjuvant trastuzumab trials.The design and efficacy of the major adjuvant trastuzumab trials was assessed, including the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group N9831, Herceptin Adjuvant, Breast Cancer International Research Group 006, and Finland Herceptin trials. The cardiotoxicity data were evaluated with a focus on the follow-up cardiac evaluations of women who were diagnosed with cardiotoxicity. Proposed mechanisms of trastuzumab-related cardiotoxicity were considered. The natural history of congestive heart failure (CHF) was reviewed with the goal of placing the trastuzumab experience in context.Up to 4% of patients enrolled onto the adjuvant trastuzumab trials experienced severe CHF during treatment. In these trials, early stopping rules that identified an unacceptable level of cardiotoxicity were never reached. Despite this, a large number of patients on these trials experienced some form of cardiotoxicity that ultimately required discontinuation of trastuzumab. Approximately 14% of patients in the NSABP B-31 trial discontinued trastuzumab because of asymptomatic decreases in left ventricular ejection fraction (LVEF). Results of follow-up cardiac evaluations of patients diagnosed with any degree of cardiotoxicity in the NSABP B-31 trial document that a clinically significant proportion of patients have sustained decrements in their LVEF to less than 50%.Adjuvant trastuzumab provides substantial benefits to patients with human epidermal growth factor receptor 2-positive breast cancer, however, competing immediate and long-term cardiovascular risks are a great concern. Continued cardiac follow-up of these women is of critical importance.

View details for DOI 10.1200/JCO.2007.11.0106

View details for Web of Science ID 000248744300023

View details for PubMedID 17687157
Phyllodes tumors of the breast: natural history, diagnosis, and treatment. Journal of the National Comprehensive Cancer Network Telli, M. L., Horst, K. C., Guardino, A. E., Dirbas, F. M., Carlson, R. W. 2007; 5 (3): 324-330
Abstract

Phyllodes tumors of the breast are unusual fibroepithelial tumors that exhibit a wide range of clinical behavior. These tumors are categorized as benign, borderline, or malignant based on a combination of histologic features. The prognosis of phyllodes tumors is favorable, with local recurrence occurring in approximately 15% of patients overall and distant recurrence in approximately 5% to 10% overall. Wide excision with a greater than 1 cm margin is definitive primary therapy. Adjuvant systemic therapy is of no proven value. Patients with locally recurrent disease should undergo wide excision of the recurrence with or without subsequent radiotherapy.

View details for PubMedID 17439760
Epidermal growth factor and angiotensin II regulation of extracellular signal-regulated protein kinase in rat liver epithelial WB cells BIOCHEMICAL PHARMACOLOGY Yang, L. J., Guo, Y. L., Trygankova, O., Li, Q. Y., Maloney, J. A., Steinhauer, M., Williamson, J. R. 1999; 57 (4): 425-432
Abstract

Activation of extracellular signal-regulated protein kinase (ERK) is considered essential for mitogenesis. In the present study, rat liver epithelial WB cells were used to investigate the relative roles of Ca2+, protein kinase C (PKC), and protein tyrosine phosphorylation in mitogenesis and activation of the ERK pathway stimulated by epidermal growth factor (EGF) and angiotensin II (Ang II). The sensitivity of the ERK pathway to Ca2+ was studied by using 1,2-bis (O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) to chelate intracellular Ca2+ and a low extracellular Ca2+ concentration to prevent Ca2+ influx. Agonist-induced PKC activation was diminished by inhibition of PKC by GF-109203X (bisindolylmaleimide) or by down-regulation of PKC by long-term treatment of the cells with phorbol myristate acetate (PMA). Our results show that although activation of PKC was critical for mitogenesis induced by Ang II or EGF, the initial activation of ERK by both agonists in these cells was essentially independent of PKC activation and was insensitive to Ca2+ mobilization. This is in contrast to the findings in some cell types that exhibit a marked dependency on mobilization of Ca2+ and/or PKC activation. On the other hand, an obligatory tyrosine phosphorylation step for activation of ERK was indicated by the use of protein tyrosine kinase inhibitors, which profoundly inhibited the activation of ERK by EGF, Ang II, and PMA. Additional experiments indicated that tyrosine phosphorylation by a cytosolic tyrosine kinase may represent a general mechanism for G-protein coupled receptor mediated ERK activation.

View details for Web of Science ID 000078201600012

View details for PubMedID 9933031

Melinda L. Telli, M.D.

Associate Professor of Medicine (Oncology) at the Stanford University Medical Center

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About
Stanford Medicine

About
Stanford Medicine