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Featured researches published by Rita A. Sakr.


Nature Genetics | 2013

ESR1 ligand-binding domain mutations in hormone-resistant breast cancer

Weiyi Toy; Yang Shen; Helen H. Won; Bradley Green; Rita A. Sakr; Marie Will; Zhiqiang Li; Kinisha Gala; Sean W. Fanning; Tari A. King; Clifford A. Hudis; David J. Chen; Tetiana Taran; Gabriel N. Hortobagyi; Geoffrey L. Greene; Michael F. Berger; José Baselga; Sarat Chandarlapaty

Seventy percent of breast cancers express estrogen receptor (ER), and most of these are sensitive to ER inhibition. However, many such tumors for unknown reasons become refractory to inhibition of estrogen action in the metastatic setting. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases. These included highly recurrent mutations encoding p.Tyr537Ser, p.Tyr537Asn and p.Asp538Gly alterations. Molecular dynamics simulations suggest that the structures of the Tyr537Ser and Asp538Gly mutants involve hydrogen bonding of the mutant amino acids with Asp351, thus favoring the agonist conformation of the receptor. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists. These data implicate LBD-mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may be of substantial therapeutic benefit.


Journal of Clinical Oncology | 2011

Clinical Management Factors Contribute to the Decision for Contralateral Prophylactic Mastectomy

Tari A. King; Rita A. Sakr; Sujata Patil; Inga Gurevich; Michelle Stempel; Michelle Sampson; Monica Morrow

PURPOSE To determine whether increasing rates of contralateral prophylactic mastectomy (CPM) are due to recognition of risk factors for contralateral breast cancer (CBC) or treatment factors related to the index lesion. METHODS From 1997 to 2005, 2,965 patients with stage 0 to III primary unilateral breast cancer underwent mastectomy at Memorial Sloan-Kettering Cancer Center. Patients who did and did not undergo CPM within 1 year of treatment for their index cancer were compared to identify independent predictors of CPM. RESULTS The rate of CPM was 13.8% (n = 407), increasing from 6.7% in 1997 to 24.2% in 2005 (P < .0001). Patients with BRCA mutations or prior mantle radiation (n = 52) accounted for 13% of those having CPM. The rate of CPM by surgeon varied from 1% to 26%. Multivariate logistic regression adjusting for surgeon-identified white race (odds ratio [OR] = 3.3), immediate reconstruction (OR = 3.3), family history of breast cancer (OR = 2.9), magnetic resonance imaging (MRI) at diagnosis (OR = 2.8), age younger than 50 years (OR = 2.2), noninvasive histology (OR = 1.8), and prior attempt at breast conversation (OR = 1.7) to be independent predictors of CPM. CONCLUSION These data suggest that increasing use of CPM is not associated with increased recognition of patients at high risk for CBC. Treatment factors, such as immediate reconstruction, preoperative MRI, and unsuccessful attempts at breast conservation, are associated with increased rates of CPM. Efforts to optimize breast conservation, minimize unnecessary tests, and improve patient education about the low risk of CBC may help to curb this trend.


Clinical Cancer Research | 2012

Frequent Mutational Activation of the PI3K-AKT Pathway in Trastuzumab-Resistant Breast Cancer

Sarat Chandarlapaty; Rita A. Sakr; Dilip Giri; Sujata Patil; Adriana Heguy; Monica Morrow; Shanu Modi; Larry Norton; Neal Rosen; Clifford A. Hudis; Tari A. King

Purpose: HER2-amplified breast cancer is sometimes clinically insensitive to HER2-targeted treatment with trastuzumab. Laboratory models of resistance have causally implicated changes in HER2 expression and activation of the phosphoinositide 3-kinase (PI3K)–AKT pathway. We conducted a prospective tissue acquisition study to determine if there is evidence for these lesions in metastatic tumors that have progressed on trastuzumab-containing therapy. Experimental Design: From 2/2007 to 11/2011, 63 patients with HER2-amplified breast cancer with recurrence of disease after adjuvant trastuzumab therapy or World Health Organization–defined progression of metastatic disease on a trastuzumab-containing regimen were prospectively enrolled and underwent tumor biopsy. Specimens were analyzed for activating mutations in PIK3CA and HER2 by Sequenom and analyzed for HER2 and PTEN status by immunohistochemistry. Results: In 53/60 cases (88%, 3 cases not evaluable for HER2), HER2 overexpression persisted in the metastatic tumor following trastuzumab exposure. Among the 7 cases lacking HER2 overexpression, repeat analysis of the pretreatment tumor failed to confirm HER2 overexpression in five cases. Among cases evaluable for PTEN (56) or PI3K mutation (45), absent or significantly diminished PTEN expression was noted in 33 (59%) and activating mutations in PIK3CA in 13 (29%). The combined rate of PTEN loss and PIK3CA mutation in the trastuzumab-refractory tumors was 71% compared with 44% (P = 0.007) in an unexposed cohort of 73 HER2-amplified tumors. Conclusions: In this series of prospectively collected trastuzumab-refractory human breast cancers, loss of HER2 overexpression was rare, whereas activation of the PI3K-AKT pathway through loss of PTEN or PIK3CA mutation was frequently observed. Clin Cancer Res; 18(24); 6784–91. ©2012 AACR.


Nature Genetics | 2014

Hotspot activating PRKD1 somatic mutations in polymorphous low-grade adenocarcinomas of the salivary glands

Ilan Weinreb; Salvatore Piscuoglio; Luciano G. Martelotto; Daryl Waggott; Charlotte K.Y. Ng; Bayardo Perez-Ordonez; Nicholas J. Harding; Javier A. Alfaro; Kenneth C. Chu; Agnes Viale; Nicola Fusco; Arnaud Da Cruz Paula; Caterina Marchiò; Rita A. Sakr; Raymond S. Lim; Lester D R Thompson; Simion I. Chiosea; Raja R. Seethala; Alena Skalova; Edward B. Stelow; Isabel Fonseca; Adel Assaad; Christine How; Jianxin Wang; Richard de Borja; Michelle Chan-Seng-Yue; Christopher J. Howlett; Anthony C. Nichols; Y Hannah Wen; Nora Katabi

Polymorphous low-grade adenocarcinoma (PLGA) is the second most frequent type of malignant tumor of the minor salivary glands. We identified PRKD1 hotspot mutations encoding p.Glu710Asp in 72.9% of PLGAs but not in other salivary gland tumors. Functional studies demonstrated that this kinase-activating alteration likely constitutes a driver of PLGA.


Molecular Oncology | 2013

Progression from ductal carcinoma in situ to invasive breast cancer: Revisited

Catherine F. Cowell; Britta Weigelt; Rita A. Sakr; Charlotte K.Y. Ng; James Hicks; Tari A. King; Jorge S. Reis-Filho

Ductal carcinoma in situ (DCIS) is an intraductal neoplastic proliferation of epithelial cells that is separated from the breast stroma by an intact layer of basement membrane and myoepithelial cells. DCIS is a non‐obligate precursor of invasive breast cancer, and up to 40% of these lesions progress to invasive disease if untreated. Currently, it is not possible to predict accurately which DCIS would be more likely to progress to invasive breast cancer as neither the significant drivers of the invasive transition have been identified, nor has the clinical utility of tests predicting the likelihood of progression been demonstrated. Although molecular studies have shown that qualitatively, synchronous DCIS and invasive breast cancers are remarkably similar, there is burgeoning evidence to demonstrate that intra‐tumor genetic heterogeneity is observed in a subset of DCIS, and that the process of progression to invasive disease may constitute an ‘evolutionary bottleneck’, resulting in the selection of subsets of tumor cells with specific genetic and/or epigenetic aberrations. Here we review the clinical challenge posed by DCIS, the contribution of the microenvironment and genetic aberrations to the progression from in situ to invasive breast cancer, the emerging evidence of the impact of intra‐tumor genetic heterogeneity on this process, and strategies to combat this heterogeneity.


Nature Genetics | 2015

In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer.

Michalina Janiszewska; Lin Liu; Vanessa Almendro; Yanan Kuang; Cloud P. Paweletz; Rita A. Sakr; Britta Weigelt; Ariella B. Hanker; Sarat Chandarlapaty; Tari A. King; Jorge S. Reis-Filho; Carlos L. Arteaga; So Yeon Park; Franziska Michor; Kornelia Polyak

Detection of minor, genetically distinct subpopulations within tumors is a key challenge in cancer genomics. Here we report STAR-FISH (specific-to-allele PCR–FISH), a novel method for the combined detection of single-nucleotide and copy number alterations in single cells in intact archived tissues. Using this method, we assessed the clinical impact of changes in the frequency and topology of PIK3CA mutation and HER2 (ERBB2) amplification within HER2-positive breast cancer during neoadjuvant therapy. We found that these two genetic events are not always present in the same cells. Chemotherapy selects for PIK3CA-mutant cells, a minor subpopulation in nearly all treatment-naive samples, and modulates genetic diversity within tumors. Treatment-associated changes in the spatial distribution of cellular genetic diversity correlated with poor long-term outcome following adjuvant therapy with trastuzumab. Our findings support the use of in situ single cell–based methods in cancer genomics and imply that chemotherapy before HER2-targeted therapy may promote treatment resistance.


Cancer Discovery | 2012

Genomic Complexity and AKT Dependence in Serous Ovarian Cancer

Aphrothiti J. Hanrahan; Nikolaus Schultz; Maggie L. Westfal; Rita A. Sakr; Dilip Giri; Stefano Scarperi; Manickam Janikariman; Narciso Olvera; Ellen V. Stevens; Qing-Bai She; Carol Aghajanian; Tari A. King; Elisa de Stanchina; David R. Spriggs; Adriana Heguy; Barry S. Taylor; Chris Sander; Neal Rosen; Douglas A. Levine; David B. Solit

UNLABELLED Effective oncoprotein-targeted therapies have not yet been developed for ovarian cancer. To explore the role of PI3 kinase/AKT signaling in this disease, we performed a genetic and functional analysis of ovarian cancer cell lines and tumors. PI3K pathway alterations were common in both, but the spectrum of mutational changes differed. Genetic activation of the pathway was necessary, but not sufficient, to confer sensitivity to selective inhibition of AKT and cells with RAS pathway alterations or RB1 loss were resistant to AKT inhibition, whether or not they had coexistent PI3K/AKT pathway activation. Inhibition of AKT1 caused growth arrest in a subset of ovarian cell lines, but not in those with AKT3 expression, which required pan-AKT inhibition. Thus, a subset of ovarian tumors are sensitive to AKT inhibition, but the genetic heterogeneity of the disease suggests that effective treatment with AKT pathway inhibitors will require a detailed molecular analysis of each patients tumor. SIGNIFICANCE A subset of ovarian cancers exhibits AKT pathway activation and is sensitive to selective AKT inhibition. Ovarian tumors exhibit significant genetic heterogeneity and thus an individualized approach based on real-time, detailed genomic and proteomic characterization of individual tumors will be required for the successful application of PI3K/AKT pathway inhibitors in this disease.


Journal of Clinical Oncology | 2015

Lobular Carcinoma in Situ: A 29-Year Longitudinal Experience Evaluating Clinicopathologic Features and Breast Cancer Risk

Tari A. King; Melissa Pilewskie; Shirin Muhsen; Sujata Patil; Starr Koslow Mautner; Anna Park; Sabine Oskar; Elena Guerini-Rocco; Camilla Boafo; Jessica C. Gooch; Marina De Brot; Jorge S. Reis-Filho; Mary Morrogh; Victor P. Andrade; Rita A. Sakr; Monica Morrow

PURPOSE The increased breast cancer risk conferred by a diagnosis of lobular carcinoma in situ (LCIS) is poorly understood. Here, we review our 29-year longitudinal experience with LCIS to evaluate factors associated with breast cancer risk. PATIENTS AND METHODS Patients participating in surveillance after an LCIS diagnosis are observed in a prospectively maintained database. Comparisons were made among women choosing surveillance, with or without chemoprevention, and those undergoing bilateral prophylactic mastectomies between 1980 and 2009. RESULTS One thousand sixty patients with LCIS without concurrent breast cancer were identified. Median age at LCIS diagnosis was 50 years (range, 27 to 83 years). Fifty-six patients (5%) underwent bilateral prophylactic mastectomy; 1,004 chose surveillance with (n = 173) or without (n = 831) chemoprevention. At a median follow-up of 81 months (range, 6 to 368 months), 150 patients developed 168 breast cancers (63% ipsilateral, 25% contralateral, 12% bilateral), with no dominant histology (ductal carcinoma in situ, 35%; infiltrating ductal carcinoma, 29%; infiltrating lobular carcinoma, 27%; other, 9%). Breast cancer incidence was significantly reduced in women taking chemoprevention (10-year cumulative risk: 7% with chemoprevention; 21% with no chemoprevention; P < .001). In multivariable analysis, chemoprevention was the only clinical factor associated with breast cancer risk (hazard ratio, 0.27; 95% CI, 0.15 to 0.50). In a subgroup nested case-control analysis, volume of disease, which was defined as the ratio of slides with LCIS to total number of slides reviewed, was also associated with breast cancer development (P = .008). CONCLUSION We observed a 2% annual incidence of breast cancer among women with LCIS. Common clinical factors used for risk prediction, including age and family history, were not associated with breast cancer risk. The lower breast cancer incidence in women opting for chemoprevention highlights the potential for risk reduction in this population.


Clinical Cancer Research | 2016

The Genomic Landscape of Male Breast Cancers

Salvatore Piscuoglio; Charlotte K.Y. Ng; Melissa P. Murray; Elena Guerini-Rocco; Luciano G. Martelotto; Felipe C. Geyer; François-Clément Bidard; Samuel H. Berman; Nicola Fusco; Rita A. Sakr; Carey A. Eberle; Leticia De Mattos-Arruda; Gabriel S. Macedo; Muzaffar Akram; Timour Baslan; James Hicks; Tari A. King; Edi Brogi; Larry Norton; Britta Weigelt; Clifford A. Hudis; Jorge S. Reis-Filho

Purpose: Male breast cancer is rare, and its genomic landscape has yet to be fully characterized. Lacking studies in men, treatment of males with breast cancer is extrapolated from results in females with breast cancer. We sought to define whether male breast cancers harbor somatic genetic alterations in genes frequently altered in female breast cancers. Experimental Design: All male breast cancers were estrogen receptor–positive, and all but two were HER2-negative. Fifty-nine male breast cancers were subtyped by immunohistochemistry, and tumor–normal pairs were microdissected and subjected to massively parallel sequencing targeting all exons of 241 genes frequently mutated in female breast cancers or DNA-repair related. The repertoires of somatic mutations and copy number alterations of male breast cancers were compared with that of subtype-matched female breast cancers. Results: Twenty-nine percent and 71% of male breast cancers were immunohistochemically classified as luminal A–like or luminal B–like, respectively. Male breast cancers displayed a heterogeneous repertoire of somatic genetic alterations that to some extent recapitulated that of estrogen receptor (ER)-positive/HER2-negative female breast cancers, including recurrent mutations affecting PIK3CA (20%) and GATA3 (15%). ER-positive/HER2-negative male breast cancers, however, less frequently harbored 16q losses, and PIK3CA and TP53 mutations than ER-positive/HER2-negative female breast cancers. In addition, male breast cancers were found to be significantly enriched for mutations affecting DNA repair–related genes. Conclusions: Male breast cancers less frequently harbor somatic genetic alterations typical of ER-positive/HER2-negative female breast cancers, such as PIK3CA and TP53 mutations and losses of 16q, suggesting that at least a subset of male breast cancers are driven by a distinct repertoire of somatic changes. Given the genomic differences, caution may be needed in the application of biologic and therapeutic findings from studies of female breast cancers to male breast cancers. Clin Cancer Res; 22(16); 4045–56. ©2016 AACR.


Applied Immunohistochemistry & Molecular Morphology | 2010

Protocol for PTEN Expression by Immunohistochemistry in Formalin-fixed Paraffin-embedded Human Breast Carcinoma

Rita A. Sakr; Violetta Barbashina; Mary Morrogh; Sarat Chandarlapaty; Victor P. Andrade; Crispinita D. Arroyo; Narciso Olvera; Tari A. King

The PI3K/PTEN pathway plays a major role in carcinogenesis. Dysregulation of this pathway occurs frequently in breast cancer, and loss of PTEN expression is emerging as a potentially important mechanism of resistance to the widely used anti-HER2 therapy, trastuzumab. However, assays for loss of PTEN expression have suffered from lack of consistency. Here, we describe an automated and reliable protocol for PTEN protein expression by immunohistochemistry in formalin-fixed paraffin-embedded tissue that can be easily incorporated into clinical trials.

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Tari A. King

Brigham and Women's Hospital

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Victor P. Andrade

Memorial Sloan Kettering Cancer Center

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Jorge S. Reis-Filho

Memorial Sloan Kettering Cancer Center

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Monica Morrow

Memorial Sloan Kettering Cancer Center

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Dilip Giri

Memorial Sloan Kettering Cancer Center

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Sarat Chandarlapaty

Memorial Sloan Kettering Cancer Center

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Britta Weigelt

Memorial Sloan Kettering Cancer Center

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Mary Morrogh

Memorial Sloan Kettering Cancer Center

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Neal Rosen

Memorial Sloan Kettering Cancer Center

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