Suleiman Alfred Massarweh

All Publications

• Molecular characterization and mortality from breast cancer in men Massarweh, S. A., Sledge, G. W., Miller, D. P., McCullough, D., Petkov, V. I., Shak, S. AMER ASSOC CANCER RESEARCH. 2018

  View details for Web of Science ID 000425489402296

• Molecular Characterization and Mortality From Breast Cancer in Men. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Massarweh, S. A., Sledge, G. W., Miller, D. P., McCullough, D., Petkov, V. I., Shak, S. 2018: JCO2017768861

  Abstract

  Purpose Limited data exist on the molecular biology, treatment, and outcomes of breast cancer in men, and much of our understanding in this area remains largely an extrapolation from data in women with breast cancer. Materials and Methods We studied men and women with hormone receptor-positive breast cancer and the 21-gene Breast Recurrence Score (RS) results. Differences in clinical characteristics and gene expression were determined, and distribution of RS results was correlated with 5-year breast cancer-specific survival (BCSS) and overall survival. Results There were 3,806 men and 571,115 women. Men were older than women (mean age, 64.2 v 59.1 years; P < .001). RS < 18 predominated in both genders, but RS ? 31 was more frequent in men (12.4% v 7.4%; P < .001), as were very low scores (RS < 11; 33.8% v 22.1%; P < .001). Mean gene expression was higher in men for the estrogen receptor (ER), proliferation, and invasion groups. ER was lowest and progesterone receptor was highest in women younger than 50 years of age, with a progressive increase in ER with age. Men younger than 50 years of age had slightly lower ER and progesterone receptor compared with older men. Survival data were available from SEER for 322 men and 55,842 women. Five-year BCSS was 99.0% (95% CI, 99.3% to 99.9%) and 95.9% (95% CI, 87.6% to 98.7%) for men with RS < 18 and RS 18-30, respectively, and for women, it was 99.5% (95% CI, 99.4% to 99.6%) and 98.6% (95% CI, 98.4% to 98.8%), respectively. RS ? 31 was associated with an 81.0% 5-year BCSS in men (95% CI, 53.3% to 93.2%) and 94.9% 5-year BCSS (95% CI, 93.9% to 95.7%) in women. Five-year BCSS and overall survival were lower in men than in women. Conclusion This study reveals some distinctive biologic features of breast cancer in men and an important prognostic role for RS testing in both men and women.

  View details for PubMedID 29584547

• Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers. Cell death & disease Williams, M. M., Lee, L., Werfel, T., Joly, M. M., Hicks, D. J., Rahman, B., Elion, D., McKernan, C., Sanchez, V., Estrada, M. V., Massarweh, S., Elledge, R., Duvall, C., Cook, R. S. 2018; 9 (2): 21

  Abstract

  Estrogen receptor-? positive (ER?+) breast cancer accounts for approximately 70-80% of the nearly 25,0000 new cases of breast cancer diagnosed in the US each year. Endocrine-targeted therapies (those that block ER? activity) serve as the first line of treatment in most cases. Despite the proven benefit of endocrine therapies, however, ER?+ breast tumors can develop resistance to endocrine therapy, causing disease progression or relapse, particularly in the metastatic setting. Anti-apoptotic Bcl-2 family proteins enhance breast tumor cell survival, often promoting resistance to targeted therapies, including endocrine therapies. Herein, we investigated whether blockade of anti-apoptotic Bcl-2 family proteins could sensitize luminal breast cancers to anti-estrogen treatment. We used long-term estrogen deprivation (LTED) of human ER?+ breast cancer cell lines, an established model of sustained treatment with and acquired resistance to aromatase inhibitors (AIs), in combination with Bcl-2/Bcl-xL inhibition (ABT-263), finding that ABT-263 induced only limited tumor cell killing in LTED-selected cells in culture and in vivo. Interestingly, expression and activity of the Bcl-2-related factor Mcl-1 was increased in LTED cells. Genetic Mcl-1 ablation induced apoptosis in LTED-selected cells, and potently increased their sensitivity to ABT-263. Increased expression and activity of Mcl-1 was similarly seen in clinical breast tumor specimens treated with AI + the selective estrogen receptor downregulator fulvestrant. Delivery of Mcl-1 siRNA loaded into polymeric nanoparticles (MCL1 si-NPs) decreased Mcl-1 expression in LTED-selected and fulvestrant-treated cells, increasing tumor cell death and blocking tumor cell growth. These findings suggest that Mcl-1 upregulation in response to anti-estrogen treatment enhances tumor cell survival, decreasing response to therapeutic treatments. Therefore, strategies blocking Mcl-1 expression or activity used in combination with endocrine therapies would enhance tumor cell death.

  View details for PubMedID 29343814

• Breast Cancer in Men Textbook of Uncommon Cancer Massarweh, S. A., Sledge, G. W. John Wiley & Sons. 2017; 5th edition: 364?374
• Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance MOLECULAR CANCER RESEARCH Malorni, L., Giuliano, M., Migliaccio, I., Wang, T., Creighton, C. J., Lupien, M., Fu, X., Hilsenbeck, S. G., Healy, N., De Angelis, C., Mazumdar, A., Trivedi, M. V., Massarweh, S., Gutierrez, C., De Placido, S., Jeselsohn, R., Brown, M., Brown, P. H., Osborne, C. K., Schiff, R. 2016; 14 (5): 470-481

  Abstract

  The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program.AP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470-81. ©2016 AACR.

  View details for DOI 10.1158/1541-7786.MCR-15-0423

  View details for Web of Science ID 000375852900006

  View details for PubMedID 26965145

  View details for PubMedCentralID PMC4867274

• Special considerations in the evaluation and management of breast cancer in men CURRENT PROBLEMS IN CANCER Massarweh, S. A., Choi, G. L. 2016; 40 (2-4): 163-171

  View details for DOI 10.1016/j.currproblcancer.2016.09.003

  View details for Web of Science ID 000390980500008

  View details for PubMedID 27793424

• Endocrine therapy and strategies to overcome therapeutic resistance in breast cancer CURRENT PROBLEMS IN CANCER Mancuso, M. R., Massarweh, S. A. 2016; 40 (2-4): 95-105

  View details for DOI 10.1016/j.currproblcancer.2016.09.001

  View details for Web of Science ID 000390980500002

  View details for PubMedID 27839747

• Everolimus-Induced Hematologic Changes in Patients With Metastatic Breast Cancer. Clinical breast cancer Chen, A., Chen, L., Al-Qaisi, A., Romond, E., Awasthi, M., Kadamyan-Melkumyan, V., Massarweh, S. 2014

  Abstract

  Everolimus, which inhibits the mammalian target of rapamycin (mTOR), is increasingly used in breast cancer and familiarity with its full range of toxicity is critical for practicing oncologists.We studied hematologic changes in 31 patients with metastatic breast cancer treated in a phase II clinical trial using everolimus. Complete blood counts were collected at baseline, 2 weeks, 4 weeks, every 4 weeks during treatment, and 1 month after discontinuation. Adverse events were defined using Common Toxicity Criteria version 3. Linear mixed models with fixed effects of time and random intercepts and slopes were used to study trends and comparisons were conducted using paired t tests.Anemia was reported in 22 patients (71%), thrombocytopenia in 17 (55%), and leukopenia in 14 (45%). These were predominantly grade 1 or 2 and did not require dose modification. Red blood cell mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) both decreased significantly over time (P < .0001) starting at 2 weeks with no significant change in mean corpuscular hemoglobin concentration (MCHC) (P = .104). Both MCV and MCH increased 1 month after treatment discontinuation (P values < .0001 and .0003, respectively) indicating reversibility of this effect. Although total leukocyte counts remained largely stable, lymphocyte percentage progressively decreased over time with a trend for increased neutrophils.In addition to anemia, leukopenia, and thrombocytopenia, everolimus consistently induces red cell microcytosis and reduced hemoglobin content. Lymphopenia may contribute to immune suppression and increased risk of infection. Familiarity with these hematologic changes is prudent as more patients are treated with this class of drugs.

  View details for DOI 10.1016/j.clbc.2014.07.002

  View details for PubMedID 25199576

• Impact of estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) co-expression on breast cancer disease characteristics: implications for tumor biology and research. Breast cancer research and treatment Alqaisi, A., Chen, L., Romond, E., Chambers, M., Stevens, M., Pasley, G., Awasthi, M., Massarweh, S. 2014; 148 (2): 437?44

  Abstract

  ER and HER2 are critical drivers of breast cancer biology and can interact when co-expressed, but less data describe the impact of ER/HER2 co-expression on clinical disease characteristics. We studied the impact of ER and HER2 (co)-expression in a cohort of 1,187 patients with invasive breast cancer and compared disease characteristics among different groups according to ER and HER2 status. Age, tumor size, grade, nodal status, TNM stage, and metastatic sites were compared and significance determined using the appropriate t tests. All p values were two-tailed. Compared to ER-negative/HER2-negative disease as the control group, ER expression was associated with older age, smaller tumors, lower grade, earlier TNM stage, and increased bone involvement in de novo metastasis, while HER2 had no significant impact on these characteristics. ER and HER2 co-expression was associated with lower grade and higher bone involvement in de novo metastasis, reflecting a retained impact for ER. HER2 impact on ER-positive disease was reflected by younger age, higher grade and TNM stage, and increased frequency of visceral involvement in de novo metastasis. Within the ER-positive/HER2-positive group, triple positive breast cancer (ER+/PgR+/HER2+) was associated with younger age compared to ER+/PgR-/HER2+ disease (mean age of 50.8 vs. 56 years, p = 0.0226). PgR was also associated with younger age in ER+/HER2- disease with a mean age of 57.6 years in ER+/PgR+/HER2- disease vs. 63.4 years in ER+/PgR-/HER2- disease (p < 0.0001). In conclusion, ER has a profound impact on breast cancer characteristics, including a retained impact when co-expressed with HER2. Similarly, HER2 dramatically modulates ER-positive breast cancer making it more aggressive. PgR association with young age may be related to hormonal levels of the premenopausal state, with HER2 providing an earlier growth advantage in triple positive disease, suggesting a specific dependence for this subset on high estrogen levels.

  View details for DOI 10.1007/s10549-014-3145-x

  View details for PubMedID 25257728

• Impact of adding the multikinase inhibitor sorafenib to endocrine therapy in metastatic estrogen receptor-positive breast cancer. Future oncology (London, England) Massarweh, S., Moss, J., Wang, C., Romond, E., Slone, S., Weiss, H., Karabakhtsian, R. G., Napier, D., Black, E. P. 2014; 10 (15): 2435?48

  Abstract

  ABSTRACT? Background: Targeting growth factor and survival pathways may delay endocrine-resistance in estrogen receptor-positive breast cancer.A pilot Phase II study adding sorafenib to endocrine therapy in 11 patients with metastatic estrogen receptor-positive breast cancer was conducted. Primary end point was response by RECIST after 3 months of sorafenib. Secondary end points included safety, time to progression and biomarker modulation. The study closed early owing to slow accrual.Eight out of 11 patients had progressive disease on study entry and three had stable disease. Of the ten evaluable patients, seven experienced stable disease (70%) and three experienced progressive diseas (30%), with a median time to progression of 6.1 months (8.4 months in the seven patients on tamoxifen). The serum samples demonstrated a significant reduction in VEGF receptor 2 and PDGF receptor-?. Microarray analysis identified 32 suppressed genes, no induced genes and 29 enriched Kyoto Encyclopedia of Genes and Genomes pathways.The strategy of adding a targeted agent to endocrine therapy upon resistance may be worthwhile testing in larger studies.

  View details for DOI 10.2217/fon.14.99

  View details for PubMedID 24826798

• A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor (ER)-positive breast cancer after aromatase inhibitor (AI) failure BREAST CANCER RESEARCH AND TREATMENT Massarweh, S., Romond, E., Black, E. P., Van Meter, E., Shelton, B., Kadamyan-Melkumian, V., Stevens, M., Elledge, R. 2014; 143 (2): 325-332

  Abstract

  Fulvestrant, which degrades ER, is used after AI failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using everolimus to inhibit mTOR, a key signaling pathway in endocrine resistance, may delay fulvestrant resistance in patients and thus improve its efficacy. We conducted a phase II trial of combined fulvestrant and everolimus in postmenopausal women with disease progression or relapse after an AI. Primary endpoint was time to progression (TTP) and secondary endpoints included objective response rate, clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were collected and biopsy of accessible tumor was done for future biomarker analysis. Of 33 patients enrolled two were ruled ineligible after enrollment and were excluded from study analysis, for a total of 31 evaluable patients. Median age was 54 years (range 45-85). Prior therapy included tamoxifen (81 %), chemotherapy (71 %), with 26 % of patients having received 3 or more endocrine agents. Median TTP was 7.4 months (95 % CI 1.9-12.1) with an objective response rate of 13 % and CBR of 49 %. Of particular note, 32 % of patients exhibited de novo resistance to study treatment with disease progression as their best response. Most common adverse events (AEs) were elevated AST (87 %) and ALT (77 %), anemia (74 %), hyperglycemia (71 %), and hypercholesterolemia (68 %). Prominent clinical toxicities were mucositis (58 %), weight loss (48 %), and rash (42 %). Most AEs were grade 1 or 2 and largely reversible with infrequent need for everolimus dose reduction. To conclude, everolimus plus fulvestrant is effective after AI failure in heavily pretreated metastatic ER-positive breast cancer and has manageable toxicity. Further study of this combination is warranted in randomized studies. Since not all patients experience benefit, and in view of potential toxicities, biomarker examination is critical to help select patients most likely to benefit from this strategy in future studies.

  View details for DOI 10.1007/s10549-013-2810-9

  View details for Web of Science ID 000329364200011

  View details for PubMedID 24327334

• ErbB3 downregulation enhances luminal breast tumor response to antiestrogens JOURNAL OF CLINICAL INVESTIGATION Morrison, M. M., Hutchinson, K., Williams, M. M., Stanford, J. C., Balko, J. M., Young, C., Kuba, M. G., Sanchez, V., Williams, A. J., Hicks, D. J., Arteaga, C. L., Prat, A., Perou, C. M., Earp, H. S., Massarweh, S., Cook, R. S. 2013; 123 (10): 4329-4343

  Abstract

  Aberrant regulation of the erythroblastosis oncogene B (ErbB) family of receptor tyrosine kinases (RTKs) and their ligands is common in human cancers. ErbB3 is required in luminal mammary epithelial cells (MECs) for growth and survival. Since breast cancer phenotypes may reflect biological traits of the MECs from which they originate, we tested the hypothesis that ErbB3 drives luminal breast cancer growth. We found higher ERBB3 expression and more frequent ERBB3 gene copy gains in luminal A/B breast cancers compared with other breast cancer subtypes. In cell culture, ErbB3 increased growth of luminal breast cancer cells. Targeted depletion of ErbB3 with an anti-ErbB3 antibody decreased 3D colony growth, increased apoptosis, and decreased tumor growth in vivo. Treatment of clinical breast tumors with the antiendocrine drug fulvestrant resulted in increased ErbB3 expression and PI3K/mTOR signaling. Depletion of ErbB3 in fulvestrant-treated tumor cells reduced PI3K/mTOR signaling, thus decreasing tumor cell survival and tumor growth. Fulvestrant treatment increased phosphorylation of all ErbB family RTKs; however, phospho-RTK upregulation was not seen in tumors treated with both fulvestrant and anti-ErbB3. These data indicate that upregulation of ErbB3 in luminal breast cancer cells promotes growth, survival, and resistance to fulvestrant, thus suggesting ErbB3 as a target for breast cancer treatment.

  View details for DOI 10.1172/JCI66764

  View details for Web of Science ID 000325443100028

  View details for PubMedID 23999432

• Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies BREAST CANCER RESEARCH AND TREATMENT Chen, A. C., Migliaccio, I., Rimawi, M., Lopez-Tarruella, S., Creighton, C. J., Massarweh, S., Huang, C., Wang, Y., Batra, S. K., Gutierrez, M. C., Osborne, C. K., Schiff, R. 2012; 134 (2): 583-593

  Abstract

  We studied resistance to endocrine and HER2-targeted therapies using a xenograft model of estrogen receptor positive (ER)/HER2-overexpressing breast cancer. Here, we report a novel phenotype of drug resistance in this model. MCF7/HER2-18 xenografts were treated with endocrine therapy alone or in combination with lapatinib and trastuzumab (LT) to inhibit HER2. Archival tumor tissues were stained with hematoxylin and eosin and with mucicarmine. RNA extracted from tumors at early time points and late after acquired resistance were analyzed for mucin4 (MUC4) expression by microarray and quantitative reverse transcriptase-PCR. Protein expression of the MUC4, ER, and HER2 signaling pathways was measured by immunohistochemistry and western blotting. The combination of the potent anti-HER2 regimen LT with either tamoxifen (Tam + LT) or estrogen deprivation (ED + LT) can cause complete eradication of ER-positive/HER2-overexpressing tumors in mice. Tumors developing resistance to this combination, as well as those acquiring resistance to endocrine therapy alone, exhibited a distinct histological and molecular phenotype-a striking increase in mucin-filled vacuoles and upregulation of several mucins including MUC4. At the onset of resistance, MUC4 mRNA and protein were increased. These tumors also showed upregulation and reactivation of HER2 signaling, while losing ER protein and the estrogen-regulated gene progesterone receptor. Mucins are upregulated in a preclinical model of ER-positive/HER2-overexpressing breast cancer as resistance develops to the combination of endocrine and anti-HER2 therapy. These mucin-rich tumors reactivate the HER2 pathway and shift their molecular phenotype to become more ER-negative/HER2-positive.

  View details for DOI 10.1007/s10549-012-2082-9

  View details for Web of Science ID 000306730500012

  View details for PubMedID 22644656

• Pathologic Changes in Breast Cancer After Anti-Estrogen Therapy BREAST JOURNAL Samarnthai, N., Elledge, R., Prihoda, T. J., Huang, J., Massarweh, S., Yeh, I. 2012; 18 (4): 362-366

  Abstract

  Breast cancer patients do not commonly receive anti-estrogens prior to surgical excision. We reviewed a cohort of patients who received preoperative anti-estrogen therapy after baseline biopsy and then had a repeat biopsy after several weeks on treatment. Patients with estrogen receptor positive tumors received anastrozole and fulvestrant in combination with gefitinib. Core needle biopsies were performed at day 1 and 21, and tumors were completely excised if operable at day 112. All patients were postmenopausal. Following treatment, tumors had degenerative changes including smudged nuclei, decreased nuclear size, intranuclear vacuoles, vacuolated cytoplasm, and increased cellular discohesion. In addition, increased tubule formation and intracytoplasmic lumina were seen in 6/9 cases (66.7%) and decreased mitotic rate was demonstrated in 7/9 cases (77.8%). These findings indicate increased differentiation of the tumor cells in response to anti-estrogen therapy and that may correlate with clinical response.

  View details for DOI 10.1111/j.1524-4741.2012.01251.x

  View details for Web of Science ID 000305968600012

  View details for PubMedID 22616615

• A phase II neoadjuvant trial of anastrozole, fulvestrant, and gefitinib in patients with newly diagnosed estrogen receptor positive breast cancer BREAST CANCER RESEARCH AND TREATMENT Massarweh, S., Tham, Y. L., Huang, J., Sexton, K., Weiss, H., Tsimelzon, A., Beyer, A., Rimawi, M., Cai, W. Y., Hilsenbeck, S., Fuqua, S., Elledge, R. 2011; 129 (3): 819-827

  Abstract

  Endocrine therapy in patients with breast cancer can be limited by the problem of resistance. Preclinical studies suggest that complete blockade of the estrogen receptor (ER) combined with inhibition of the epidermal growth factor receptor can overcome endocrine resistance. We tested this hypothesis in a phase II neoadjuvant trial of anastrozole and fulvestrant combined with gefitinib in postmenopausal women with newly diagnosed ER-positive breast cancer. After a baseline tumor core biopsy, patients were randomized to receive anastrozole and fulvestrant or anastrozole, fulvestrant, and gefitinib (AFG) for 3 weeks. After a second biopsy at 3 weeks, all patients received AFG for 4 months and surgery was done if the tumor was operable. The primary endpoint was best clinical response by RECIST criteria and secondary endpoints were toxicity and change in biomarkers. The study closed after 15 patients were enrolled because of slow accrual. Median patient age was 67 years and median clinical tumor size was 7 cm. Four patients had metastatic disease present. Three patients withdrew before response was assessed. In the remaining 12 patients, there were two complete clinical responses (17%), three partial responses (25%), five had stable disease (41%), and two (17%) had progressive disease. Most common adverse events were rash in four patients, diarrhea in four, joint symptoms in three, and abnormal liver function tests in three. There were no grade 4 toxicities and all toxicities were reversible. At 3 weeks, cell proliferation as measured by Ki-67 was significantly reduced in the AFG group (P value = 0.01), with a parallel reduction in the expression of the Cyclin D1 (P value = 0.02). RNA microarray data showed a corresponding decrease in the expression of cell cycle genes. These results suggest that AFG was an effective neoadjuvant therapy and consistently reduced proliferation in ER-positive tumors.

  View details for DOI 10.1007/s10549-011-1679-8

  View details for Web of Science ID 000294680600015

  View details for PubMedID 21792626

• Reduced Dose and Intermittent Treatment with Lapatinib and Trastuzumab for Potent Blockade of the HER Pathway in HER2/neu-Overexpressing Breast Tumor Xenografts CLINICAL CANCER RESEARCH Rimawi, M. F., Wiechmann, L. S., Wang, Y., Huang, C., Migliaccio, I., Wu, M., Gutierrez, C., Hilsenbeck, S. G., Arpino, G., Massarweh, S., Ward, R., Soliz, R., Osborne, C. K., Schiff, R. 2011; 17 (6): 1351-1361

  Abstract

  We have shown that incomplete blockade of the human epidermal growth factor (HER) pathway is a mechanism of resistance to treatment with trastuzumab (T) in HER2-overexpressing tumor xenografts. We now investigate whether the addition of lapatinib (L), a dual HER1/2 kinase inhibitor, to T results in more potent inhibition of the pathway and therefore inhibition of tumor growth, and whether reduced dose and intermittent treatment with the combination is equally effective.Nude mice bearing HER2-overexpressing MCF7/HER2-18 or BT-474 xenograft tumors were treated with L and T, alone or in various combinations with other HER inhibitors. L + T for short duration (14 and 42 days), intermittent administration (14 days on/off), and reduced dosing (half dose) was also investigated. Inhibition of tumor growth, downstream signaling, proliferation, and induction of apoptosis were assessed. All statistical tests were two-sided.L + T was the most effective regimen in both MCF7/HER2-18 and BT-474 xenografts with complete regression (CR) of tumor observed in all mice. Intermittent and reduced dose treatment (½ dose) resulted in high rates of CR and low rates of tumor recurrence that were comparable to full dose continuous treatment. L + T resulted in significantly reduced downstream signaling and proliferation, and increased apoptosis.L + T is a potent and effective combination even when given in reduced dose or intermittent schedule potentially resulting in lower toxicity and reduced cost if translated to patients. These findings warrant timely clinical testing.

  View details for DOI 10.1158/1078-0432.CCR-10-1905

  View details for Web of Science ID 000288435300016

  View details for PubMedID 21138857

• Development of resistance to targeted therapies transforms the clinically associated molecular profile subtype of breast tumor xenografts CANCER RESEARCH Creighton, C. J., Massarweh, S., Huang, S., Tsimelzon, A., Hilsenbeck, S. G., Osborne, C. K., Shou, J., Malorni, L., Schiff, R. 2008; 68 (18): 7493-7501

  Abstract

  The effectiveness of therapies targeting specific pathways in breast cancer, such as the estrogen receptor or HER2, is limited because many tumors manifest resistance, either de novo or acquired, during the course of treatment. To investigate molecular mechanisms of resistance, we used two xenograft models of estrogen receptor-positive (ER+) breast cancer, one with and one without HER2 overexpression (MCF7/HER2-18 and MCF7 wt, respectively). Mice with established tumors were assigned to the following treatment groups: estrogen supplementation (E2), estrogen deprivation (ED), ED plus tamoxifen (Tam), all with or without the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (G). Another group received ED plus the antiestrogen fulvestrant (MCF7 wt only). Tumors with acquired or de novo resistance to these endocrine therapies were profiled for gene expression and compared with tumors in the E2 control group. One class of genes underexpressed in endocrine-resistant tumors (relative to E2-treated tumors) were estrogen inducible in vitro and associated with ER+ human breast cancers (luminal subtype). Another class of genes overexpressed in tumors with acquired resistance in both models represented transcriptional targets of HER2 signaling and was associated with ER-/HER2+ human cancers (ERBB2+ subtype). A third class of genes overexpressed in MCF7/HER2-18 tumors exhibiting de novo resistance to tamoxifen was associated with ER+ human cancers but not with estrogen-regulated genes. Thus, in response to various endocrine therapy regimens, these xenograft breast tumors shut down classic estrogen signaling and activate alternative pathways such as HER2 that contribute to treatment resistance. Over time, the molecular phenotype of breast cancer can change.

  View details for DOI 10.1158/0008-5472.CAN-08-1404

  View details for Web of Science ID 000259422400031

  View details for PubMedID 18794137

• Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function CANCER RESEARCH Massarweh, S., Osborne, C. K., Creighton, C. J., Qin, L., Tsimelzon, A., Huang, S., Weiss, H., Rimawi, M., Schiff, R. 2008; 68 (3): 826-833

  Abstract

  Not all breast cancers respond to tamoxifen, and many develop resistance despite initial benefit. We used an in vivo model of estrogen receptor (ER)-positive breast cancer (MCF-7 xenografts) to investigate mechanisms of this resistance and develop strategies to circumvent it. Epidermal growth factor receptor (EGFR) and HER2, which were barely detected in control estrogen-treated tumors, increased slightly with tamoxifen and were markedly increased when tumors became resistant. Gefitinib, which inhibits EGFR/HER2, improved the antitumor effect of tamoxifen and delayed acquired resistance, but had no effect on estrogen-stimulated growth. Phosphorylated levels of p42/44 and p38 mitogen-activated protein kinases (both downstream of EGFR/HER2) were increased in the tamoxifen-resistant tumors and were suppressed by gefitinib. There was no apparent increase in phosphorylated AKT (also downstream of EGFR/HER2) in resistant tumors, but it was nonetheless suppressed by gefitinib. Phosphorylated insulin-like growth factor-IR (IGF-IR), which can interact with both EGFR and membrane ER, was elevated in the tamoxifen-resistant tumors compared with the sensitive group. However, ER-regulated gene products, including total IGF-IR itself and progesterone receptor, remained suppressed even at the time of acquired resistance. Tamoxifen's antagonism of classic ER genomic function was retained in these resistant tumors and even in tumors that overexpress HER2 (MCF-7 HER2/18) and are de novo tamoxifen-resistant. In conclusion, EGFR/HER2 may mediate tamoxifen resistance in ER-positive breast cancer despite continued suppression of ER genomic function by tamoxifen. IGF-IR expression remains dependent on ER but is activated in the tamoxifen-resistant tumors. This study provides a rationale to combine HER inhibitors with tamoxifen in clinical studies, even in tumors that do not initially overexpress EGFR/HER2.

  View details for DOI 10.1158/0008-5472.CAN-07-2707

  View details for Web of Science ID 000252952900027

  View details for PubMedID 18245484

• Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy JOURNAL OF THE NATIONAL CANCER INSTITUTE Arpino, G., Gutierrez, C., Weiss, H., Rimawi, M., Massarweh, S., Bharwani, L., De Placido, S., Osborne, C. K., Schiff, R. 2007; 99 (9): 694-705

  Abstract

  Human epidermal growth factor receptor 2 (HER2) is a member of the HER signaling pathway. HER inhibitors partially block HER signaling and tumor growth in preclinical breast cancer models. We investigated whether blockade of all HER homo- and heterodimer pairs by combined treatment with several inhibitors could more effectively inhibit tumor growth in such models.Mice carrying xenograft tumors of HER2-overexpressing MCF7/HER2-18 (HER2-transfected) or BT474 (HER2-amplified) cells were treated with estrogen supplementation or estrogen withdrawal, alone or combined with tamoxifen. One to three HER inhibitors (pertuzumab, trastuzumab, or gefitinib) could also be added (n > or = 8 mice per group). Tumor volumes, HER signaling, and tumor cell proliferation and apoptosis were assessed. Results were analyzed with the t test or Wilcoxon rank sum test and survival analysis methods. All statistical tests were two-sided.Median time to tumor progression was 21 days for mice receiving estrogen and 28 days for mice receiving estrogen and pertuzumab (difference = 7 days; P = .001; hazard ratio [HR] of progression in mice receiving estrogen and pertuzumab versus mice receiving estrogen = 0.27, 95% confidence interval [CI] = 0.09 to 0.77). Addition of gefitinib and trastuzumab to estrogen and pertuzumab increased this time to 49 days (difference = 21 days; P = .004; HR of progression = 0.28, 95% CI = 0.10 to 0.76). MCF7/HER2-18 tumors disappeared completely and did not progress (for > or = 189 days) after combination treatment with pertuzumab, trastuzumab, and gefitinib plus tamoxifen (19 of 20 mice) or plus estrogen withdrawal (14 of 15 mice). Both combination treatments induced apoptosis and blocked HER signaling and proliferation in tumor cells better than any single agent or dual combination. All BT474 tumors treated with pertuzumab, trastuzumab, and gefitinib disappeared rapidly, regardless of endocrine therapy, and no tumor progression was observed for 232 days.Combined treatment with gefitinib, trastuzumab, and pertuzumab to block signals from all HER homo- and heterodimers inhibited growth of HER2-overexpressing xenografts statistically significantly better than single agents and dual combinations.

  View details for DOI 10.1093/jnci/djk151

  View details for Web of Science ID 000246352500009

  View details for PubMedID 17470737

• Unraveling the mechanisms of endocrine resistance in breast cancer: New therapeutic opportunities CLINICAL CANCER RESEARCH Massarweh, S., Schiff, R. 2007; 13 (7): 1950-1954

  Abstract

  Two thirds of breast cancers express the estrogen receptor (ER), which contributes to tumor development and progression. ER-targeted therapy is therefore widely used in breast cancer to inhibit signaling through ER and disrupt breast cancer growth. This therapeutic strategy, particularly using the antiestrogen tamoxifen, is proven to increase the cure rates in early breast cancer, improve patient outcomes in advanced disease, and reduce breast cancer incidence in the prevention setting. Despite the recent integration of more powerful endocrine agents into breast cancer care, resistance to all forms of endocrine therapy remains a major problem. New insight into ER biology and progress in understanding resistance mechanisms, mediated by molecular crosstalk between ER and various growth factor signaling pathways, are generating tremendous promise for new therapeutic opportunities to target resistance and improve breast cancer disease outcomes.

  View details for DOI 10.1158/1078-0432.CCR-06-2540

  View details for Web of Science ID 000245660800002

  View details for PubMedID 17404074

• Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk 2nd Tenovus/AstraZeneca Workshop on Growth Factor Signalling Pathways in Cancer Progression Massarweh, S., Schiff, R. SOC ENDOCRINOLOGY. 2006: S15?S24

  Abstract

  Targeting the estrogen receptor (ER) is the oldest form of molecular targeted therapy, and the widespread use of the selective estrogen receptor modulator tamoxifen in breast cancer is responsible for major improvements in cure rates, quality of life, and disease prevention in the last 25 years. Newer forms of endocrine therapy now available for the management of endocrine responsive breast cancer include a new generation of aromatase inhibitors, which lower the estrogen ligand for ER, and pure ER antagonists which destroy the receptor. Despite these recent clinical advances, intrinsic and acquired resistance to these endocrine therapies is still a common feature that limits the success of this therapeutic strategy. Recent research into the molecular biology of ER signaling has revealed a remarkably complex interactive signaling with other growth factor signaling pathways in breast cancer cells, potentially explaining some of the reasons behind endocrine therapy action as well as resistance. This view of a more complex ER signaling system has uncovered new molecular targets which, if present in a cancer cell, might be additionally targeted using various signal transduction inhibitors to overcome or prevent resistance to endocrine therapy. In addition, the dynamic inverse relationship between the expression of ER and growth factor receptors brings more excitement to the potential of restoring ER expression in apparently ER-negative cells by inhibition of growth factor signaling. Ongoing clinical trials of endocrine therapy combined with growth factor pathway inhibitors or their downstream signaling elements promise to further improve the present care for breast cancer patients.

  View details for DOI 10.1677/erc.1.01273

  View details for Web of Science ID 000243887500003

  View details for PubMedID 17259554

• Mechanisms of tumor regression and resistance to estrogen deprivation and fulvestrant in a model of estrogen receptor-positive, HER-2/neu-positive breast cancer CANCER RESEARCH Massarweh, S., Osborne, C. K., Jiang, S., Wakeling, A. E., Rimawi, M., Mohsin, S. K., Hilsenbeck, S., Schiff, R. 2006; 66 (16): 8266-8273

  Abstract

  HER-2/neu in breast cancer is associated with tamoxifen resistance, but little data exist on its interaction with estrogen deprivation or fulvestrant. Here, we used an in vivo xenograft model of estrogen receptor (ER)-positive breast cancer with HER-2/neu overexpression (MCF7/HER-2/neu-18) to investigate mechanisms of growth inhibition and treatment resistance. MCF7/HER-2/neu-18 tumors were growth inhibited by estrogen deprivation and with fulvestrant, but resistance developed in 2 to 3 months. Inhibited tumors had reductions in ER, insulin-like growth factor-I receptor (IGF-IR), phosphorylated HER-2/neu (p-HER-2/neu), and phosphorylated p42/44 mitogen-activated protein kinase (p-MAPK). p27 was increased especially in tumors sensitive to estrogen deprivation. Tumors with acquired resistance to these therapies had complete loss of ER, increased p-HER-2/neu, increased p-MAPK, and reduced p27. In contrast, IGF-IR and phosphorylated AKT (p-AKT) levels were markedly reduced in these resistant tumors. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib, which can block EGFR/HER-2/neu signaling, significantly delayed the emergence of resistance to both estrogen deprivation and fulvestrant. Levels of p-MAPK and p-AKT decreased with gefitinib, whereas high ER levels were restored. Eventually, however, tumors progressed in mice treated with gefitinib combined with estrogen deprivation or fulvestrant accompanied again by loss of ER and IGF-IR, increased p-HER-2/neu, high p-MAPK, and now increased p-AKT. Thus, estrogen deprivation and fulvestrant can effectively inhibit HER-2/neu-overexpressing tumors but resistance develops quickly. EGFR/HER-2/neu inhibitors can delay resistance, but reactivation of HER-2/neu and signaling through AKT leads to tumor regrowth. Combining endocrine therapy with EGFR/HER-2/neu inhibitors should be tested in clinical breast cancer, but a more complete blockade of EGFR/HER-2/neu may be optimal.

  View details for DOI 10.1158/0008-5472.CAN-05-4045

  View details for Web of Science ID 000239828200056

  View details for PubMedID 16912207

• Mechanisms of tamoxifen resistance: Increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer JOURNAL OF THE NATIONAL CANCER INSTITUTE Shou, J., Massarweh, S., Osborne, C. K., Wakeling, A. E., Ali, S., Weiss, H., Schiff, R. 2004; 96 (12): 926-935

  Abstract

  Patients receiving adjuvant tamoxifen whose tumors express high levels of both HER2/neu (HER2) and the estrogen receptor (ER) coactivator AIB1 often develop tamoxifen resistance. We used a breast cancer model system with high expression of AIB1 and HER2 to investigate the possible mechanisms underlying this resistance.MCF-7 breast cancer cells, which express high levels of AIB1, and a tamoxifen-resistant derivative cell line engineered to overexpress HER2 (MCF-7/HER2-18) were treated with estrogen, tamoxifen, epidermal growth factor (EGF), or heregulin in the absence or presence of the EGF receptor (EGFR) tyrosine kinase inhibitor gefitinib. We analyzed phosphorylation of signaling intermediates by immunoblotting, ER transcriptional activity with reporter gene constructs and immunoblot analysis of endogenous gene products, promoter assembly by chromatin immunoprecipitation (ChIP) assay, and tumor cell growth in vitro by anchorage-independent colony formation and in vivo using xenografts in nude mice.MCF-7/HER2-18 tumors were completely growth inhibited by estrogen deprivation but were growth stimulated by tamoxifen. Molecular cross-talk between the ER and HER2 pathways was increased in the MCF-7/HER-2 cells compared with MCF-7 cells, with cross-phosphorylation and activation of both the ER and the EGFR/HER2 receptors, the signaling molecules AKT and ERK 1,2 mitogen-activated protein kinase (MAPK), and AIB1 itself with both estrogen and tamoxifen treatment. Tamoxifen recruited coactivator complexes (ER, AIB1, CBP, p300) to the ER-regulated pS2 gene promoter in MCF-7/HER2-18 cells and corepressor complexes (NCoR, histone deacetylase 3) in MCF-7 cells. Gefitinib pretreatment blocked receptor cross-talk, reestablished corepressor complexes with tamoxifen-bound ER on target gene promoters, eliminated tamoxifen's agonist effects, and restored its antitumor activity both in vitro and in vivo in MCF-7/HER2-18 cells.Tamoxifen behaves as an estrogen agonist in breast cancer cells that express high levels of AIB1 and HER2, resulting in de novo resistance. Gefitinib's ability to eliminate this cross-talk and to restore tamoxifen's antitumor effects should be tested in the clinic.

  View details for DOI 10.1093/jnci/djh166

  View details for Web of Science ID 000222340900012

  View details for PubMedID 15199112

• Evolution of genomic alterations on endocrine therapy and mTOR inhibition in estrogen receptor (ER)-positive breast cancer Massarweh, S., Romond, E., Stewart, R., Sun, J., Chmielecki, J., Mehdi, M., Black, E. P. AMER ASSOC CANCER RESEARCH. 2016

  View details for DOI 10.1158/1538-7445.SABCS15-P3-05-06

  View details for Web of Science ID 000375622400232

• Introduction to special issue on breast cancer. Current problems in cancer Massarweh, S. A. 2016

  View details for PubMedID 27793423

• Evaluation of possible linkage between everolimus benefit in estrogen receptor (ER)-positive breast cancer and genomic alterations of the PI3K/AKT/mTOR pathway. Black, E. P., Romond, E. H., Chmielecki, J., Sun, J., Kadamyan, V., Chambers, M. D., Stewart, R., Dressler, E., Mehdi, M., Horbinski, C., Massarweh, S. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for DOI 10.1200/jco.2015.33.15_suppl.530

  View details for Web of Science ID 000358036901137

• Metastatic angiosarcoma and kasabach-merritt syndrome. Rare tumors Massarweh, S., Munis, A., Karabakhtsian, R., Romond, E., Moss, J. 2014; 6 (2): 5366-?

  Abstract

  Angiosarcomas are exceedingly rare tumors that are often difficult to diagnose. Exceptionally unusual is the presentation of these tumors with Kasabach-Merritt Syndrome, a curious form of intratumoral coagulation that can be impossible to distinguish from intravascular coagulation, which is more common. Instant recognition of this clinical association can help making a prompt diagnosis and timely initiation of therapy.

  View details for DOI 10.4081/rt.2014.5366

  View details for PubMedID 25002952

• Blastic plasmacytoid dendritic cell neoplasm with extensive cutaneous and central nervous system involvement. Rare tumors Saeed, H., Awasthi, M., Al-Qaisi, A., Massarweh, S. 2014; 6 (4): 5474

  Abstract

  Blastic plasmacytoid dendritic neoplasm is an exceedingly rare tumor that has undergone several changes in nomenclature over the last two decades, largely because of confusion regarding its cell of origin. It does, however, have distinctive clinical features with a particularly aggressive clinical course and no standard treatment. Overall, prognosis is poor and relapse is routine after initial response to chemotherapy. In this report, we describe a typical patient with this disease and reconcile the available literature and its evolution. We emphasize the leukemic nature of this tumor's behavior, with extensive central nervous system and skin involvement, and describe for the first time a potential role for maintenance chemotherapy in its treatment.

  View details for DOI 10.4081/rt.2014.5474

  View details for PubMedID 25568744

• Prevalence of hormone receptors and HER2/neu in breast cancer cases in Jordan 16th Meeting of the Arab Division of the International-Academy-of-Pathology Sughayer, M. A., Al-Khawaja, M. M., Massarweh, S., Al-Masri, M. SPRINGER. 2006: 83?86

  Abstract

  The management and prognosis of breast cancer nowadays require the evaluation of Estrogen (ER), Progesterone Receptors (PR) and HER2/neu. Ethnic variation in the expression of these receptors is well documented. The aim of this study is to determine the prevalence of ER, PR and HER2/neu among Jordanian women with breast cancer of ductal and lobular types. A retrospective analysis was performed on 267 cases of breast cancer referred for treatment at King Hussein Cancer Center, Jordan between the period of June 2003 and June 2004. Standard immune stains were used for evaluation of hormone receptors and HER2/neu. In addition, evaluation of HER2/neu was done by FISH in selected cases. Of these 267 cases, 240 (89.9%) were ductal carcinomas of various histological grades, 122 (50.8%) of which were ER-positive, 138 (57.5%) PRpositive and 42 (17.5%) HER2/neu-positive. Twentytwo (8.2%) of all cases were lobular carcinomas, 15 (68%) of which were ER-positive, 20 (90.9%) PRpositive and 3 (13.6%) HER2/neu-positive. Five (1.9%) of the total cases were of mixed lobular and ductal types, 4 (80%) of which were ER-positive, 3 (60%) PR-positive and none were positive for HER2/neu. The prevalence of hormone receptor positivity in breast cancer of Jordanian women is lower than that of the western populations and close to other populations such as the Chinese and the minor ethnic groups of Northern America (African Americans).

  View details for Web of Science ID 000239140500004

  View details for PubMedID 16799708

• Advanced concepts in estrogen receptor biology and breast cancer endocrine resistance: implicated role of growth factor signaling and estrogen receptor coregulators. Cancer chemotherapy and pharmacology Schiff, R., Massarweh, S. A., Shou, J., Bharwani, L., Arpino, G., Rimawi, M., Osborne, C. K. 2005; 56: 10-20

  Abstract

  Estrogen receptor (ER), mediating estrogen-signaling stimuli, is a dominant regulator and a key therapeutic target in breast cancer etiology and progression. Endocrine therapy, blocking the ER pathway, is one of the most important systemic therapies in breast cancer management, but de novo and acquired resistance is still a major clinical problem. New research highlights the role of both genomic and nongenomic ER activities and their intimate molecular crosstalk with growth factor receptor and other signaling kinase pathways in endocrine resistance. These signaling pathways, when overexpressed and/or hyperactivated, can modulate both activities of ER, resulting in endocrine resistance. Thus, these signal transduction receptors and signaling molecules may serve as both predictive markers and novel therapeutic targets to circumvent endocrine resistance. Compelling experimental and clinical evidence suggest that the epidermal growth factor/HER2/neu receptor (EGFR/HER2) pathway might play a distinct role in endocrine resistance, and especially in resistance to selective estrogen receptor modulators (SERMs) such as tamoxifen. Results from preclinical studies of treatment combinations with various endocrine therapy drugs together with several potent anti-EGFR/HER2 inhibitors are very promising, and clinical trials to see whether this new strategy is effective in patients are now ongoing.

  View details for PubMedID 16273359

• Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer 4th International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer Osborne, C. K., Shou, J., Massarweh, S., Schiff, R. AMER ASSOC CANCER RESEARCH. 2005: 865S?870S

  Abstract

  Data suggest that breast cancer growth is regulated by coordinated actions of the estrogen receptor (ER) and various growth factor receptor signaling pathways. In tumors with active growth factor receptor signaling (e.g., HER2 amplification), tamoxifen may lose its estrogen antagonist activity and may acquire more agonist-like activity, resulting in tumor growth stimulation. Because treatments designed to deprive the ER of its ligand estrogen will reduce signaling from both nuclear and membrane ER, aromatase inhibitors might be expected to be superior to tamoxifen in tumors with high growth factor receptor content, such as those overexpressing HER2. Recent clinical studies suggest that this is the case in humans, as trials of aromatase inhibitors show superior results compared with tamoxifen, especially in tumors overexpressing HER2. Although estrogen deprivation therapy is often effective in ER-positive breast cancer, de novo and acquired resistance are still problematic. Experimental models suggest that in one form of resistance to estrogen deprivation therapy, the tumor becomes supersensitive to low residual estrogen concentrations perhaps because of activation of mitogen-activated protein kinase. Such tumors respond to additional treatment with fulvestrant or even tamoxifen. On the other hand, in tumors overexpressing HER2, acquired resistance to estrogen deprivation therapy involves the loss of ER and ER-regulated genes and further up-regulation of growth factor signaling rendering the tumor hormonal therapy resistant. This process can be delayed or reversed by simultaneous treatment with growth factor pathway inhibitors. This strategy is now being tested in clinical trials.

  View details for Web of Science ID 000226525100002

  View details for PubMedID 15701879

• Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance 3rd International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer Schiff, R., Massarweh, S. A., Shou, J., Bharwani, L., Mohsin, S. K., Osborne, C. K. AMER ASSOC CANCER RESEARCH. 2004: 331S?336S

  Abstract

  Introduced more than 100 years ago, endocrine therapy is still the most important systemic therapy for all stages of estrogen receptor (ER) -positive breast tumors. A major clinical problem limiting the usefulness of this therapy is tumor resistance, either de novo or acquired during the course of the treatment. Relatively new discoveries emphasize the complexity of ER signaling and its multiple regulatory interactions with growth factor and other kinase signaling pathways. Both genomic (nuclear) and nongenomic (membrane and cytoplasmic) ER activities contribute to this intimate cross-talk, which is probably a fundamental factor in endocrine resistance. New targeted therapies, especially against the epidermal growth factor receptor/HER-2 pathway, should be carefully evaluated in more (bio)logical strategies to enable them to be exploited appropriately. A strategy of combining endocrine therapy (particularly tamoxifen) with these inhibitors, to circumvent de novo and acquired resistance, will be discussed. We will also emphasize open questions and future challenges in the dynamic research field of molecular ER biology from the endocrine therapy perspective.

  View details for Web of Science ID 000188424000002

  View details for PubMedID 14734488