I am a physician-scientist and currently a Breast Pathology Fellow (AP-3, Anatomic Pathology only program) at the Department of Pathology of the Stanford University School of Medicine/Stanford Healthcare with a particular clinical interest in Breast Pathology and Molecular Genetic Pathology and a research interest in the development of new quantitative approaches to pathology to accurately predict the development of cancer, correctly classify tumors by prognosis and predict response to cancer therapy, leveraging biomedical informatics and computational pathology tools to inquire large datasets of clinical and genomics data, mostly focusing on breast cancer.

Honors & Awards

  • Arthur Purdy Stout Stipend Award, Arthur Purdy Stout Society of Surgical Pathologists (2018)
  • Charles B. Carrington Memorial Prize, Department of Pathology, Stanford University School of Medicine (2017)
  • Trainee Mentored Award in Precision Health, Department of Pathology, Stanford University School of Medicine (2017)
  • Junior Career and Development Award, Harvard Medical School - Portugal Program (2013)

Professional Education

  • Clinical Fellowship, Stanford University School of Medicine / Stanford Healthcare, Breast Pathology
  • Residency, Stanford University School of Medicine / Stanford Healthcare, Residency in Pathology
  • Postdoctoral Fellowship, Harvard Medical School / Beth Israel Deaconess Medical Center, Bioinformatics (2016)
  • Postdoctoral Fellowship, Harvard Medical School/Dana-Farber Cancer Institute, Oncology (2015)
  • Graduate Certificate Program, Harvard Medical School - Portugal Program, Clinical Scholars Research Certificate Training Program (Clinical Research) (2013)
  • PhD, University of Porto, Faculty of Medicine, Oncology and Molecular Medicine (2017)
  • MD/MSc, University of Porto, Faculty of Medicine (2009)


All Publications

  • Whole-Exome and RNA-Sequencing Analyses of Acinic Cell Carcinomas of the Breast. Histopathology Beca, F., Lee, S. S., Pareja, F., da Cruz Paula, A., Selenica, P., Ferrando, L., Gularte-Merida, R., Wen, H. Y., Zhang, H., Guerini-Rocco, E., Rakha, E. A., Weigelt, B., Reis-Filho, J. S. 2019


    Acinic cell carcinoma of the breast (ACC) is a rare histologic form of triple-negative breast cancer (TNBC). Despite its unique histology, targeted sequencing analysis has failed to identify recurrent genetic alterations other than those found in common forms of TNBC. Here, we subjected three breast ACCs to whole-exome and RNA-sequencing, seeking to define whether they would harbor a pathognomonic genetic alteration.Tumor and normal DNA and RNA samples from three breast ACCs were subjected to whole-exome sequencing. Somatic mutations, copy number alterations, mutational signatures and fusion genes were determined using state-of-the-art bioinformatics methods. Our analyses revealed TP53 hotspot mutations associated with loss of heterozygosity of the wild-type allele in two cases. Mutations affecting homologous recombination (HR) DNA repair-related genes were found in two cases, and an MLH1 pathogenic germline variant was detected in one case. In addition, copy number analysis revealed the presence of a somatic BRCA1 homozygous deletion and focal amplification of 12q14.3-12q21.1, encompassing MDM2, HMGA2, FRS2 and PTPRB. No oncogenic in-frame fusion transcript was identified in the three breast ACCs analyzed.No pathognomonic genetic alterations were detected in the ACCs analyzed. These tumors have somatic genetic alterations similar to those of common forms of TNBC and may display HR deficiency or microsatellite instability. These findings provide further insights as to why ACCs which are usually clinically indolent may evolve into or in parallel with high-grade TNBC. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/his.13962

    View details for PubMedID 31361912

  • EZH2 protein expression in normal breast epithelium and risk of breast cancer: results from the Nurses' Health Studies BREAST CANCER RESEARCH Beca, F., Kensler, K., Glass, B., Schnitt, S. J., Tamimi, R. M., Beck, A. H. 2017; 19


    Enhancer of zeste homolog 2 (EZH2) is a polycomb-group protein that is involved in stem cell renewal and carcinogenesis. In breast cancer, increased EZH2 expression is associated with aggressiveness and has been suggested to identify normal breast epithelium at increased risk of breast cancer development. However, the association between EZH2 expression in benign breast tissue and breast cancer risk has not previously been evaluated in a large prospective cohort.We examined the association between EZH2 protein expression and subsequent breast cancer risk using logistic regression in a nested case-control study of benign breast disease (BBD) and breast cancer within the Nurses' Health Studies. EZH2 immunohistochemical expression in normal breast epithelium and stroma was evaluated by computational image analysis and its association with breast cancer risk was analyzed after adjusting for matching factors between cases and controls, the concomitant BBD diagnosis, and the Ki67 proliferation index.Women with a breast biopsy in which more than 20% of normal epithelial cells expressed EZH2 had a significantly increased risk of developing breast cancer (odds ratio (OR) 2.95, 95% confidence interval (CI) 1.11-7.84) compared to women with less than 10% EZH2 epithelial expression. The risk of developing breast cancer increased for each 5% increase in EZH2 expression (OR 1.22, 95% CI 1.02-1.46, p value 0.026). Additionally, women with high EZH2 expression and low estrogen receptor (ER) expression had a 4-fold higher risk of breast cancer compared to women with low EZH2 and low ER expression (OR 4.02, 95% CI 1.29-12.59).These results provide further evidence that EZH2 expression in the normal breast epithelium is independently associated with breast cancer risk and might be used to assist in risk stratification for women with benign breast biopsies.

    View details for DOI 10.1186/s13058-017-0817-6

    View details for Web of Science ID 000396919900001

    View details for PubMedID 28253895

    View details for PubMedCentralID PMC5335498

  • Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nature medicine Dai, X., Gan, W., Li, X., Wang, S., Zhang, W., Huang, L., Liu, S., Zhong, Q., Guo, J., Zhang, J., Chen, T., Shimizu, K., Beca, F., Blattner, M., Vasudevan, D., Buckley, D. L., Qi, J., Buser, L., Liu, P., Inuzuka, H., Beck, A. H., Wang, L., Wild, P. J., Garraway, L. A., Rubin, M. A., Barbieri, C. E., Wong, K. K., Muthuswamy, S. K., Huang, J., Chen, Y., Bradner, J. E., Wei, W. 2017


    The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3(SPOP) earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.

    View details for DOI 10.1038/nm.4378

    View details for PubMedID 28805820

  • Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition. Cancer discovery Gil Del Alcazar, C. R., Huh, S. J., Ekram, M. B., Trinh, A., Liu, L. L., Beca, F., Zi, X., Kwak, M., Bergholtz, H., Su, Y., Ding, L., Russnes, H. G., Richardson, A. L., Babski, K., Min Hui Kim, E., McDonnell, C., Wagner, J., Rowberry, R., Freeman, G. J., Dillon, D., Sorlie, T., Coussens, L. M., Garber, J. E., Fan, R., Bobolis, K., Allred, D. C., Jeong, J., Park, S. Y., Michor, F., Polyak, K. 2017


    To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS recurrent IDC. TCR clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT expressing T cells were more frequent in DCIS whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple negative IDCs. Co-amplification of 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show co-evolution of cancer cells and the immune microenvironment during tumor progression.

    View details for PubMedID 28652380

  • Diagnostic Assessment of Deep Learning Algorithms for Detection of Lymph Node Metastases in Women With Breast Cancer. JAMA Ehteshami Bejnordi, B., Veta, M., Johannes van Diest, P., van Ginneken, B., Karssemeijer, N., Litjens, G., van der Laak, J. A., Hermsen, M., Manson, Q. F., Balkenhol, M., Geessink, O., Stathonikos, N., van Dijk, M. C., Bult, P., Beca, F., Beck, A. H., Wang, D., Khosla, A., Gargeya, R., Irshad, H., Zhong, A., Dou, Q., Li, Q., Chen, H., Lin, H. J., Heng, P. A., Haß, C., Bruni, E., Wong, Q., Halici, U., Öner, M. Ü., Cetin-Atalay, R., Berseth, M., Khvatkov, V., Vylegzhanin, A., Kraus, O., Shaban, M., Rajpoot, N., Awan, R., Sirinukunwattana, K., Qaiser, T., Tsang, Y. W., Tellez, D., Annuscheit, J., Hufnagl, P., Valkonen, M., Kartasalo, K., Latonen, L., Ruusuvuori, P., Liimatainen, K., Albarqouni, S., Mungal, B., George, A., Demirci, S., Navab, N., Watanabe, S., Seno, S., Takenaka, Y., Matsuda, H., Ahmady Phoulady, H., Kovalev, V., Kalinovsky, A., Liauchuk, V., Bueno, G., Fernandez-Carrobles, M. M., Serrano, I., Deniz, O., Racoceanu, D., Venāncio, R. 2017; 318 (22): 2199?2210


    Application of deep learning algorithms to whole-slide pathology images can potentially improve diagnostic accuracy and efficiency.Assess the performance of automated deep learning algorithms at detecting metastases in hematoxylin and eosin-stained tissue sections of lymph nodes of women with breast cancer and compare it with pathologists' diagnoses in a diagnostic setting.Researcher challenge competition (CAMELYON16) to develop automated solutions for detecting lymph node metastases (November 2015-November 2016). A training data set of whole-slide images from 2 centers in the Netherlands with (n?=?110) and without (n?=?160) nodal metastases verified by immunohistochemical staining were provided to challenge participants to build algorithms. Algorithm performance was evaluated in an independent test set of 129 whole-slide images (49 with and 80 without metastases). The same test set of corresponding glass slides was also evaluated by a panel of 11 pathologists with time constraint (WTC) from the Netherlands to ascertain likelihood of nodal metastases for each slide in a flexible 2-hour session, simulating routine pathology workflow, and by 1 pathologist without time constraint (WOTC).Deep learning algorithms submitted as part of a challenge competition or pathologist interpretation.The presence of specific metastatic foci and the absence vs presence of lymph node metastasis in a slide or image using receiver operating characteristic curve analysis. The 11 pathologists participating in the simulation exercise rated their diagnostic confidence as definitely normal, probably normal, equivocal, probably tumor, or definitely tumor.The area under the receiver operating characteristic curve (AUC) for the algorithms ranged from 0.556 to 0.994. The top-performing algorithm achieved a lesion-level, true-positive fraction comparable with that of the pathologist WOTC (72.4% [95% CI, 64.3%-80.4%]) at a mean of 0.0125 false-positives per normal whole-slide image. For the whole-slide image classification task, the best algorithm (AUC, 0.994 [95% CI, 0.983-0.999]) performed significantly better than the pathologists WTC in a diagnostic simulation (mean AUC, 0.810 [range, 0.738-0.884]; P?

    View details for PubMedID 29234806

  • Precision Cancer Diagnostics: Tracking Genomic Evolution in Clinical Trials PLOS MEDICINE Beca, F., Beck, A. H. 2016; 13 (12)


    In a Perspective, Francisco Beca and Andrew Beck discuss Charles Swanton and colleagues' accompanying Research Article on somatic mutations in patients with inflammatory breast cancer treated in a Phase II clinical trial.

    View details for DOI 10.1371/journal.pmed.1002177

    View details for Web of Science ID 000392142400004

    View details for PubMedID 27923047

    View details for PubMedCentralID PMC5140044

  • Predicting breast tumor proliferation from whole-slide images: The TUPAC16 challenge MEDICAL IMAGE ANALYSIS Veta, M., Heng, Y. J., Stathonikos, N., Bejnordi, B., Beca, F., Wollmann, T., Rohr, K., Shah, M. A., Wang, D., Rousson, M., Hedlund, M., Tellez, D., Ciompi, F., Zerhouni, E., Lanyi, D., Viana, M., Kovalev, V., Liauchuk, V., Phoulady, H., Qaiser, T., Graham, S., Rajpoot, N., Sjoblom, E., Molin, J., Paeng, K., Hwang, S., Park, S., Jia, Z., Chang, E., Xu, Y., Beck, A. H., van Diest, P. J., Pluim, J. W. 2019; 54: 111?21
  • SPOP Promotes Nanog Destruction to Suppress Stem Cell Traits and Prostate Cancer Progression DEVELOPMENTAL CELL Zhang, J., Chen, M., Zhu, Y., Dai, X., Dang, F., Ren, J., Ren, S., Shulga, Y. V., Beca, F., Gan, W., Wu, F., Lin, Y., Zhou, X., DeCaprio, J. A., Beck, A. H., Lu, K., Huang, J., Zhao, C., Sun, Y., Gao, X., Pandolfi, P., Wei, W. 2019; 48 (3): 329-+
  • EN1 is a transcriptional dependency in triple-negative breast cancer associated with brain metastasis. Cancer research Peluffo, G., Subedee, A., Harper, N. W., Kingston, N., Jovanovi?, B., Flores, F., Stevens, L. E., Beca, F., Trinh, A., Reddy Chilamakuri, C. S., Papachristou, E. K., Murphy, K., Su, Y., Marusyk, A., D'Santos, C. S., Rueda, O. M., Beck, A. H., Caldas, C., Carroll, J. S., Polyak, K. 2019


    To define transcriptional dependencies of triple-negative breast cancer (TNBC), we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that EN1 (Engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance as direct EN1 transcriptional targets. Quantitative proteomic analyses of EN1-bound chromatin complexes revealed association with transcriptional repressors and co-activators including TLE3, TRIM24, TRIM28, and TRIM33. High expression of EN1 correlated with short overall survival and increased risk of developing brain metastases in TNBC patients. Thus, EN1 is a prognostic marker and a potential therapeutic target in TNBC.

    View details for DOI 10.1158/0008-5472.CAN-18-3264

    View details for PubMedID 31239270

  • Ancillary Tests in Breast Cytology: A Practical Guide. Acta cytologica Beca, F., Schmitt, F. C. 2019: 1?12


    Utilization of fine-needle aspiration biopsy (FNAB) cytology for the diagnosis of diseases of the breast has been met with both excitement and uncertainty during the last couple of decades. Presently, FNAB for the diagnosis of primary and metastatic breast lesions is on the rise again. This is probably due to its fast turnaround time, cost efficiency, and minimal invasiveness, characteristics of this sampling modality which are particularly crucial for patients requiring frequent repeat biopsy in the setting of metastatic lesions. In this article, we will briefly review the main modern applications of FNAB of the breast when coupled with contemporary ancillary techniques. Such contemporary ancillary techniques range from classic immunocytochemistry (ICC) to the most modern molecular techniques, particularly next-generation sequencing. Coupled with contemporary ICC and molecular methods, FNAB of the breast can be used for several applications. The applications reviewed in this article include the primary diagnosis of a breast lesion, the identification of the breast as a primary source of a metastatic lesion, the evaluation of breast prognostic/predictive markers, and the tracking of tumor evolution. In our opinion, FNAB of the breast is an ideal sampling method, sharing many of the advantages of truly liquid and of tissue biopsies. Ultimately, we aim at demystifying the complexity of many of the challenges traditionally associated with the application of ancillary techniques to FNAB of the breast and provide insights into some of the most cutting-edge and clinically useful application scenarios.

    View details for DOI 10.1159/000499697

    View details for PubMedID 31141801

  • Outcome of radial scar/complex sclerosing lesion associated with epithelial proliferations with atypia diagnosed on breast core biopsy: results from a multicentric UK-based study. Journal of clinical pathology Rakha, E., Beca, F., D'Andrea, M., Abbas, A., Petrou-Nunn, W., Shaaban, A. M., Kandiyil, A., Smith, S., Menon, S., Elsheikh, S., ElSayed, M. E., Lee, A. S., Sharma, N. 2019


    The clinical significance of radial scar (RS)/complex sclerosing lesion (CSL) with high-risk lesions (epithelial atypia) diagnosed on needle core biopsy is not well defined. We aimed at assessing the upgrade rate to ductal carcinoma in situ (DCIS) and invasive carcinoma on the surgical excision specimen in a large cohort with RS/CSL associated with atypia.157 women with a needle core biopsy diagnosis of a RS/CSL with atypia and follow-up histology were studied. Histological findings, including different forms of the atypical lesions and final histological outcome in the excision specimens, were retrieved and analysed, and the upgrade rates for malignancy and for invasive carcinoma wwere calculated.69.43% of the cases were associated with atypical ductal hyperplasia (ADH) or atypia not otherwise classifiable, whereas lobular neoplasia was seen in 21.66%. On final histology, 39 cases were malignant (overall upgrade rate of 24.84%); 12 were invasive and 27 had DCIS. The upgrade differed according to the type of atypia and was highest for ADH (35%). When associated with lobular neoplasia, the upgrade rate was 11.76%. The upgrade rate's variability was also considerably lower when considering the upgrade to invasive carcinoma alone for any associated lesion.The upgrade rate for ADH diagnosed on needle core biopsy with RS is similar to that of ADH without RS and therefore should be managed similarly. RS associated with lobular neoplasia is less frequently associated with malignant outcome. Most lesions exhibiting some degree of atypia showed a similar upgrade rate to invasive carcinoma. Management of RS should be based on the concurrent atypical lesion.

    View details for DOI 10.1136/jclinpath-2019-205764

    View details for PubMedID 31350292

  • Androgen receptor expression in normal breast tissue and subsequent breast cancer risk NPJ BREAST CANCER Kensler, K. H., Beca, F., Baker, G. M., Heng, Y. J., Beck, A. H., Schnitt, S. J., Hazra, A., Rosner, B. A., Eliassen, A., Hankinson, S. E., Brown, M., Tamimi, R. M. 2018; 4
  • The clinicopathologic and genomic features of fibrotic foci in breast cancer - results from the TCGA cohort Beca, F., Tsang, J., Jensen, K. C., Allison, K., Tse, G. NATURE PUBLISHING GROUP. 2018: 50
  • Molecular Cytology Applications in Metastases Molecular Applications in Cytology Beca, F., Schmitt, F. Springer Nature Switzerland AG. 2018; 1: 247?259
  • Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling CANCER RESEARCH Henry, W. S., Laszewski, T., Tsang, T., Beca, F., Beck, A. H., McAllister, S. S., Toker, A. 2017; 77 (3): 790-801


    Despite the high incidence of oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K, PI3K inhibitors have yielded little clinical benefit for breast cancer patients. Recent epidemiologic studies have suggested a therapeutic benefit from aspirin intake in cancers harboring oncogenic PIK3CA Here, we show that mutant PIK3CA-expressing breast cancer cells have greater sensitivity to aspirin-mediated growth suppression than their wild-type counterparts. Aspirin decreased viability and anchorage-independent growth of mutant PIK3CA breast cancer cells independently of its effects on COX-2 and NF-?B. We ascribed the effects of aspirin to AMP-activated protein kinase (AMPK) activation, mTORC1 inhibition, and autophagy induction. In vivo, oncogenic PIK3CA-driven mouse mammary tumors treated daily with aspirin resulted in decreased tumor growth kinetics, whereas combination therapy of aspirin and a PI3K inhibitor further attenuated tumor growth. Our study supports the evaluation of aspirin and PI3K pathway inhibitors as a combination therapy for targeting breast cancer. Cancer Res; 77(3); 790-801. ©2016 AACR.

    View details for DOI 10.1158/0008-5472.CAN-16-2400

    View details for Web of Science ID 000393194400019

    View details for PubMedID 27940576

    View details for PubMedCentralID PMC5290090

  • Dieulafoy?s Lesion Pathology of the Gastrointestinal Tract Beca, F., Rios, E. edited by Carneiro, F., Chaves, P., Ensari, A. Springer International Publishing. 2017; 1: 177?179
  • LINC00520 is induced by Src, STAT3, and PI3K and plays a functional role in breast cancer ONCOTARGET Henry, W. S., Hendrickson, D. G., Beca, F., Glass, B., Lindahl-Allen, M., He, L., Ji, Z., Struhl, K., Beck, A. H., Rinn, J. L., Toker, A. 2016; 7 (50): 81981-81994


    Long non-coding RNAs (lncRNAs) have been implicated in normal cellular homeostasis as well as pathophysiological conditions, including cancer. Here we performed global gene expression profiling of mammary epithelial cells transformed by oncogenic v-Src, and identified a large subset of uncharacterized lncRNAs potentially involved in breast cancer development. Specifically, our analysis revealed a novel lncRNA, LINC00520 that is upregulated upon ectopic expression of oncogenic v-Src, in a manner that is dependent on the transcription factor STAT3. Similarly, LINC00520 is also increased in mammary epithelial cells transformed by oncogenic PI3K and its expression is decreased upon knockdown of mutant PIK3CA. Additional expression profiling highlight that LINC00520 is elevated in a subset of human breast carcinomas, with preferential enrichment in the basal-like molecular subtype. ShRNA-mediated depletion of LINC00520 results in decreased cell migration and loss of invasive structures in 3D. RNA sequencing analysis uncovers several genes that are differentially expressed upon ectopic expression of LINC00520, a significant subset of which are also induced in v-Src-transformed MCF10A cells. Together, these findings characterize LINC00520 as a lncRNA that is regulated by oncogenic Src, PIK3CA and STAT3, and which may contribute to the molecular etiology of breast cancer.

    View details for DOI 10.18632/oncotarget.11962

    View details for Web of Science ID 000391352800005

    View details for PubMedID 27626181

    View details for PubMedCentralID PMC5347668

  • MicroRNA signatures in cytopathology: Are they ready for prime time? CANCER CYTOPATHOLOGY Beca, F., Schmitt, F. 2016; 124 (9): 613-615

    View details for DOI 10.1002/cncy.21728

    View details for Web of Science ID 000383685600003

    View details for PubMedID 27153190

  • Intratumor Heterogeneity in Breast Cancer NOVEL BIOMARKERS IN THE CONTINUUM OF BREAST CANCER Beca, F., Polyak, K. 2016; 882: 169-189


    Intratumor heterogeneity is the main obstacle to effective cancer treatment and personalized medicine. Both genetic and epigenetic sources of intratumor heterogeneity are well recognized and several technologies have been developed for their characterization. With the technological advances in recent years, investigators are now elucidating intratumor heterogeneity at the single cell level and in situ. However, translating the accumulated knowledge about intratumor heterogeneity to clinical practice has been slow. We are certain that better understanding of the composition and evolution of tumors during disease progression and treatment will improve cancer diagnosis and the design of therapies. Here we review some of the most important considerations related to intratumor heterogeneity. We discuss both genetic and epigenetic sources of intratumor heterogeneity and review experimental approaches that are commonly used to quantify it. We also discuss the impact of intratumor heterogeneity on cancer diagnosis and treatment and share our perspectives on the future of this field.

    View details for DOI 10.1007/978-3-319-22909-6_7

    View details for Web of Science ID 000376034700008

    View details for PubMedID 26987535

  • Altered PPP2R2A and Cyclin D1 expression defines a subgroup of aggressive luminal-like breast cancer BMC CANCER Beca, F., Pereira, M., Cameselle-Teijeiro, J. F., Martins, D., Schmitt, F. 2015; 15


    PPP2R2A deletions were recently linked to a subgroup of luminal breast carcinoma (BC) that exhibits poor survival. This subgroup also exhibited amplification of a chromosome region containing the Cyclin D1 coding gene, CCND1. Therefore, we aimed to investigate whether a combination of PPP2R2A (B55?) and Cyclin D1 expression statuses evaluated by immunohistochemistry (IHC) could define a subgroup of luminal BC that exhibits poor survival.First we conducted a retrospective cohort study using sequencing data from The Cancer Genome Atlas initiative to correlate PPP2R2A copy number alteration (CNA) status with its expression level and the corresponding overall survival (OS). Next, also using a retrospective cohort study design, we evaluated the PPP2R2A (B55?) expression levels by IHC in a total of 807 BC patients from two independent cohorts (discovery cohort n = 349 and validation cohort n = 458). Cyclin D1 expression was also evaluated, and the PPP2R2A (B55?)(-/low)/Cyclin D1(high) phenotype was evaluated as a predictor of disease-free survival (DFS) and OS in luminal-like BC patients.Deletions in the PPP2R2A gene strongly correlate with lower mRNA expression and poorer OS. PPP2R2A (B55?)(-/low) carcinomas have significantly shorter DFS and OS. Furthermore, in univariate analysis, the PPP2R2A (B55?)(-/low)/Cyclin D1(high) phenotype is significantly associated with poorer DFS and OS. In a multivariate analysis, the PPP2R2A (B55?)(-/low)/Cyclin D1(high) phenotype is significantly associated with poor DFS, thus defining a group of luminal-like BC with higher risk of relapse.We demonstrate that BCs harboring PPP2R2A deletions are associated with worse OS. Moreover, this is the first study to demonstrate that the combination of altered PPP2R2A (B55?) and high Cyclin D1 expression by IHC defines a subgroup of luminal-like BC patients with a high risk of relapse and death.

    View details for DOI 10.1186/s12885-015-1266-1

    View details for Web of Science ID 000353454400002

    View details for PubMedID 25879784

    View details for PubMedCentralID PMC4409761

  • p-mTOR expression is associated with better prognosis in luminal breast carcinoma JOURNAL OF CLINICAL PATHOLOGY Beca, F., Andre, R., Martins, D. S., Bilhim, T., Martins, D., Schmitt, F. 2014; 67 (11): 961-967


    Despite considerable interest in the PI3K/AKT/mTOR pathway in breast carcinomas (BC), published data reports contradictory results regarding the association of phosphorylated mammalian target of Rapamycin (p-mTOR) expression with clinico-pathological features and prognosis in BC. Here, we evaluate the main clinico-pathological associations with p-mTOR expression in BC, with focus on the different molecular subtypes.In this retrospective study, 331 BC patients were included in final analysis. Outcome measures included disease-free survival (DFS) and overall survival (OS) times. Baseline data and outcome measures were compared between immunohistochemical p-mTOR expressing and non-expressing BCs. Subgroup analysis was performed to assess the effect of p-mTOR expression in the outcome for each BC molecular subtype.43.8% of the tumours were positive for p-mTOR, with a significant correlation between p-mTOR expression with smaller (<2 cm) (p=0.021) and lower-grade tumours (p<0.001). Expression of p-mTOR was also associated with longer DFS (HR of 0.32, p<0.001) and OS (HR of 0.20, p<0.001). In a multivariable analysis, the HR remained significant with minimal change (HR=0.26, p=0.002 for OS; HR=0.40, p=0.002 for DFS). In subgroup analysis, luminal p-mTOR-expressing tumours demonstrated longer DFS and OS (HR 0.33, p=0.003; HR 0.20, p=0.003, respectively) independently of size, grade, lymph node status and Her-2 overexpression.p-mTOR expression is associated with smaller, lower-grade and with luminal BC. In multivariable analysis, p-mTOR expression was associated with longer DFS and OS, independently of the size, grade and lymph node status, especially in luminal BCs.

    View details for DOI 10.1136/jclinpath-2014-202320

    View details for Web of Science ID 000344067700006

    View details for PubMedID 25053543

  • Genotypes and Prevalence of HPV Single and Multiple Concurrent Infections in Women with HSIL DIAGNOSTIC CYTOPATHOLOGY Beca, F., Pinheiro, J., Rios, E., Pontes, P., Amendoeira, I. 2014; 42 (11): 919-923


    The contribution of human papillomavirus (HPV) types to the carcinogenesis of cervical cancer has been established for a long time. However, the role of phylogenetically related and rare variants remains uncertain, as well as the influence of concurrent multiple HPV genotypes infection. We aimed at studying the prevalence of several HPV genotypes infecting women with single versus concurrent multiple HPV genotypes infection with a HSIL diagnosis in a cervical cytology. We conducted a cross-sectional study using Thin-Prep(®) liquid-based cervical cytology specimens with the diagnosis of high-grade squamous intraepithelial lesion (HSIL), in which HPV genotype was sequentially tested. Genotypes were determined with a PapilloCheck(®) system, a DNA-Chip for the type-specific identification of 18 high-risk and six low-risk types of HPV. Of the total study population, 176 cases had a diagnosis of HSIL and positive HPV genotyping result, being HPV16 the most prevalent genotype (48.86%; 95%CI: 41.58-56.19) followed by HPV31 (14.20%; 95%CI: 9.75-20.18). Concurrent multiple HPV genotypes were detected in 36.93% (95%CI: 30.15-44.27) of the patients. The prevalence of the 10 most common HPV genotypes detected varied significantly according to the presence of single vs. concurrent multiple HPV genotypes (P?=?0.022). Moreover, women with concurrent multiple HPV genotypes were on average 3.53 (95%CI: 0.43-6.64) years younger than women with single genotype infection. Our results suggest that women with multiple genotype HPV infection differ in terms of age and distribution of the most prevalent HPV genotypes. Additionally, we provide further evidence of the predominance of HPV16 in HSIL lesions of the uterine cervix.

    View details for DOI 10.1002/dc.23143

    View details for Web of Science ID 000343969900001

    View details for PubMedID 24623593

  • Tumor Heterogeneity: The Lernaean Hydra of Oncology? ONCOLOGY-NEW YORK Janiszewska, M., Beca, F., Polyak, K. 2014; 28 (9): 781-784

    View details for Web of Science ID 000342553000008

    View details for PubMedID 25224477

  • Metastatic breast cancer: mechanisms and opportunities for cytology CYTOPATHOLOGY Martins, D., Beca, F., Schmitt, F. 2014; 25 (4): 225-230


    Despite significant advances in diagnosis, surgical techniques, general patient care, and local and systemic adjuvant therapies, metastatic disease remains the most critical condition limiting the survival of patients with breast cancer. Therefore, the development of effective treatment against late-arising metastasis has become the centre of clinical attention and is one of the current challenges in cancer research. A deeper understanding of the metastatic cascade is fundamental, and the need for repetitive tumour assessments for the evaluation of tumour evolution is a relatively new practice in routine medical care. As such, fine needle aspiration cytology (FNAC) is ideally placed to monitor biological changes in metastasis that may affect treatment and response. As FNAC is a minimally invasive method, it can be performed repeatedly with relatively little trauma, and selective ancillary tests can be applied to FNAC specimens, including for tumour whose primary nature is known. Herein, we review how the linear and parallel models explain metastatic dissemination, thus influencing therapeutic and clinical decisions, and how cytology, together with immunocytochemistry and molecular analysis, can be a tool for routine clinical practice and clinical trials aimed at metastatic disease with a special emphasis on breast cancer.

    View details for DOI 10.1111/cyt.12158

    View details for Web of Science ID 000340667500002

    View details for PubMedID 24889678

  • Tactoid body features in a Schwann cell hamartoma of colonic mucosa INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY de Beca, F. F., Lopes, J., Macoas, F., Carneiro, F., Lopes, J. M. 2014; 22 (5): 438-441


    Mesenchymal colorectal polyps are uncommon lesions, particularly those of neurogenic origin. We describe a mucosal Schwann cell hamartoma of the colon with tactoid features, so far reported in peripheral nerve sheath tumours, and address its differential diagnosis and clinical implications.A 72-year-old man underwent screening colonoscopy that presented a 5-mm polyp on distal sigmoid. Histologically, it displayed a lesion in the lamina propria comprising oval structures with tactoid features and bland spindle cells, entrapping adjacent crypts. No ganglion cells were seen. Spindle cells expressed only S-100 protein and vimentin.Mucosal Schwann cell hamartoma was recently recognized as distinct from common (submucosal) colorectal Schwannomas and so far not associated to inherited syndromes. Thus, it should be considered in the differential diagnosis of look-alike lesions (eg, ganglioneuroma, neuroma, and neurofibroma) that may occur in the setting of inherited syndromes such as Cowden syndrome, multiple endocrine neoplasia-2B, and type 1 neurofibromatosis.

    View details for DOI 10.1177/1066896913501384

    View details for Web of Science ID 000340174500009

    View details for PubMedID 23994879

  • Growing Indication for FNA to Study and Analyze Tumor Heterogeneity at Metastatic Sites CANCER CYTOPATHOLOGY Beca, F., Schmitt, F. 2014; 122 (7): 504-511


    In routine practice, suspected metastases in patients with cancer are only occasionally biopsied, primarily because of the cost and invasiveness of the procedure. However, biopsies of metastatic lesions can be valuable, not only in confirming the presence of metastatic disease, but also in revealing unsuspected benign disease or secondary malignancies. In addition, such biopsies also allow the assessment of biomarkers that might differ from those on primary tumor cells, and can thereby facilitate selection of the optimal treatment. Because of the increasing recognition of clonal and phenotypic heterogeneity of tumors, we anticipate that in the near future, biopsying of metastatic lesions will constitute a standard-of-care practice, allowing assessment of molecular differences between the primary tumor and metastatic lesions. In our opinion, fine-needle aspiration is currently the best method for making repeated biopsies to monitor the tumor: it is minimally invasive, safe, and cost effective and can be coupled with modern ancillary techniques. Here we provide an up-to-date review of the clinical implications of tumor heterogeneity in metastatic disease and the ancillary molecular techniques used in cytology; we also discuss the role of modern cytology in contemporary diagnosis and management of metastatic cancer.

    View details for DOI 10.1002/cncy.21395

    View details for Web of Science ID 000340531400005

    View details for PubMedID 24478259

  • Primary relapse site pattern in women with triple-negative breast cancer PATHOLOGY RESEARCH AND PRACTICE Beca, F., Santos, R., Vieira, D., Zeferino, L., Dufloth, R., Schmitt, F. 2014; 210 (9): 571-575


    Despite the remarkable improvements in breast cancer (BC) characterization, accurate prediction of BC clinical behavior is often still difficult to achieve. Some studies have investigated the association between the molecular subtype, namely the basal-like BC and the pattern of relapse, however only few investigated the association between relapse pattern and immunohistochemical defined triple-negative breast cancers (TNBCs). The aim of this study was to evaluate the pattern of relapse in patients with TNBC, namely the primary distant relapse site. One-hundred twenty nine (129) invasive breast carcinomas with follow-up information were classified according to the molecular subtype using immunohistochemistry for ER, PgR and Her2. The association between TNBC and distant relapse primary site was analyzed by logistic regression. Using multivariate logistic regression analysis patients with TNBC displayed only 0.09 (95% CI: 0.00-0.74; p=0.02) the odds of the non-TNBC patients of developing bone primary relapse. Regarding visceral and lymph-node relapse, no differences between in this cohort were found. Though classically regarded as aggressive tumors, TNBCs rarely development primary relapse in bone when compared to non-TNBC, a clinical relevant fact when investigating a metastasis of an occult or non-sampled primary BC.

    View details for DOI 10.1016/j.prp.2014.05.011

    View details for Web of Science ID 000342247300006

    View details for PubMedID 24939141

  • Improved malignancy prediction by B3 breast lesions subclassification ANNALS OF DIAGNOSTIC PATHOLOGY de Beca, F. F., Rasteiro, C., Correia, A., Costa, S., Amendoeira, I. 2013; 17 (5): 434-436


    Core-needle biopsy (CNB) of breast lesions can be classified into 5 categories according to lesion type and associated risk of malignancy. B3 category (lesion of uncertain malignant potential) constitutes a challenging problem in clinical decision, with most ending in excisional biopsy. Therefore, the aim of this study was to establish the incidence of malignancy on excision biopsy of B3 lesions and assess if subclassification (in B3a and B3b categories) according to the presence of atypia in otherwise B3 lesions better predicts malignancy on excision. Forty-eight cases with diagnosis of B3 lesion on CNB and matched surgical excision specimen were included to evaluate the positive predictive value (PPV) and odds for malignancy in CNB. All cases were further subclassified into B3a and B3b categories. B3 category lesions had an overall PPV for malignancy of 12.5% and significant low odds of malignancy of 0.14. When subclassified, B3b (lesions with atypia) demonstrated a higher PPV for malignancy (36.36%) with a nonsignificant odds. Inversely, B3a (lesions without atypia) demonstrated a PPV for malignancy of only 5.41% and a significant low odds of malignancy of only 0.06. The described low rate of malignancy in some of B3 lesions additionally reinforces the practice of avoiding surgical excision in selected patients and provides data that additionally support B3 lesion subclassification according to the presence of atypia. Subclassification of B3 category can further refine the current classification of associated risk of malignancy with possible implications in clinical management.

    View details for DOI 10.1016/j.anndiagpath.2013.05.003

    View details for Web of Science ID 000324896100009

    View details for PubMedID 23773891

  • Loss of caveolin-1 and gain of MCT4 expression in the tumor stroma Key events in the progression from an in situ to an invasive breast carcinoma CELL CYCLE Martins, D., Beca, F. F., Sousa, B., Baltazar, F., Paredes, J., Schmitt, F. 2013; 12 (16): 2684-2690


    The progression from in situ to invasive breast carcinoma is still an event poorly understood. However, it has been suggested that interactions between the neoplastic cells and the tumor microenvironment may play an important role in this process. Thus, the determination of differential tumor-stromal metabolic interactions could be an important step in invasiveness. The expression of stromal Caveolin-1 (Cav-1) has already been implicated in the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Additionally, stromal Cav-1 expression has been associated with the expression of stromal monocarboxylate transporter 4 (MCT4) in invasive breast cancer. However, the role of stromal MCT4 in invasiveness has never been explored, neither the association between Cav-1 and MCT4 in the transition from breast DCIS to IDC. Therefore, our aim was to investigate in a series of breast cancer samples including matched in situ and invasive components, if there was a relationship between stromal Cav-1 and MCT4 in the progression from in situ to invasive carcinoma. We found loss of stromal Cav-1 in the progression to IDC in 75% of the cases. In contrast, MCT4 stromal expression was acquired in 87% of the IDCs. Interestingly, a concomitant loss of Cav-1 and gain of MCT4 was observed in the stroma of 75% of the cases, when matched in situ and invasive carcinomas were compared. These results suggest that alterations in Cav-1 and MCT4 may thus mark a critical point in the progression from in situ to invasive breast cancer.

    View details for DOI 10.4161/cc.25794

    View details for Web of Science ID 000326703800028

    View details for PubMedID 23907124

    View details for PubMedCentralID PMC3865058

  • Cancer stem cells markers CD44, CD24 and ALDH1 in breast cancer special histological types JOURNAL OF CLINICAL PATHOLOGY de Beca, F. F., Caetano, P., Gerhard, R., Alvarenga, C. A., Gomes, M., Paredes, J., Schmitt, F. 2013; 66 (3): 187-191


    CD44, CD24 and ALDH1 are the most consistently used biomarkers to identify and characterise the breast cancer stem cell (CSC) phenotype. However, most studies performed until now analysed samples of invasive ductal carcinomas of no special type (IDC-NST). Therefore, prevalence and clinical significance of these CSC markers in breast carcinomas of special histological types (SHT) is largely unknown. For that reason, this study aims to determine the distribution of the breast CD44, CD24 and ALDH1 CSC markers among a series of invasive breast carcinomas of SHT, in comparison with a series of IDC-NST.117 invasive SHT breast carcinomas were analysed for the expression of CD44, CD24 and ALDH1, by immuhohistochemistry. The distribution of these CSC markers was evaluated among the distinct histological special types, and the results were compared with a series of 466 IDC-NST.The expression prevalence of the breast CSC markers differed between special types and IDC-NST. Medullary, papillary and tubular carcinomas were enriched in the CSC phenotype CD44(+)/CD24(-/low) (80.0%, 100.0% and 100.0%, respectively, vs 45.3% in IDC-NST). Considering the ALDH1 cytoplasmic tumour expression, only medullary and metaplastic carcinomas displayed significant increase in CD44(+)/CD24(-/low)/ALDH1(+) CSC phenotype frequency (36.4% and 28.6%, respectively, vs 4.8% in IDC-NST).The expression distribution of breast CSC markers is largely dependent on histological type. Interestingly, within the distinct SHT, medullary and metaplastic carcinomas are the two types highly associated with high-grade carcinomas, basal-like and claudin-low molecular subtypes, and to the CSC phenotype CD44(+)/CD24(-/low)/ALDH1(+).

    View details for DOI 10.1136/jclinpath-2012-201169

    View details for Web of Science ID 000315292200003

    View details for PubMedID 23112116

  • Oral squamous cell carcinoma in a Crohn's disease patient taking azathioprine: Case report and review of the literature JOURNAL OF CROHNS & COLITIS Vilas-Boas, F., Magro, F., Balhau, R., Lopes, J. M., Beca, F., Eloy, C., Lopes, S., Macedo, G. 2012; 6 (7): 792-795


    Thiopurines are widely used for remission maintenance and post-operative recurrence prevention in Crohn's disease. The increased risk of cancer in transplant recipients on azathioprine is well recognized and there are concerns that this may also be true for inflammatory bowel disease patients. We report a case of a 33-year-old Caucasian woman with Crohn's disease treated with azathioprine for 9 years who developed an ulcerated lesion at the right superior retromolar trigone. Biopsy specimen revealed a squamous cell carcinoma.

    View details for DOI 10.1016/j.crohns.2012.03.004

    View details for Web of Science ID 000306780100009

    View details for PubMedID 22464812

  • Training does not affect exhaled nitric oxide in competitive swimmers ALLERGY Moreira, A., Delgado, L., HAAHTELA, T., SILVA, J. A., Araujo, L., Beca, F., Fonseca, J., Castel-Branco, M. G. 2008; 63 (5): 623-624

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