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1. Converging and evolving immuno-genomic routes toward immune escape in breast cancer

Author

Blanco-Heredia, Juan, Souza, Carla Anjos, Trincado, Juan L., Gonzalez-Cao, Maria, Gonçalves-Ribeiro, Samuel, Gil, Sara Ruiz, Pravdyvets, Dmytro, Cedeño, Samandhy, Callari, Maurizio, Marra, Antonio, Gazzo, Andrea M., Weigelt, Britta, Pareja, Fresia, Vougiouklakis, Theodore, Jungbluth, Achim A., Rosell, Rafael, Brander, Christian, Tresserra, Francesc, Reis-Filho, Jorge S., Tiezzi, Daniel Guimarães, de la Iglesia, Nuria, Heyn, Holger, and De Mattos-Arruda, Leticia

Published
2024
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2. Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations

Author

Dopeso, Higinio, Gazzo, Andrea M., Derakhshan, Fatemeh, Brown, David N., Selenica, Pier, Jalali, Sahar, Da Cruz Paula, Arnaud, Marra, Antonio, da Silva, Edaise M., Basili, Thais, Gusain, Laxmi, Colon-Cartagena, Lorraine, Bhaloo, Shirin Issa, Green, Hunter, Vanderbilt, Chad, Oesterreich, Steffi, Grabenstetter, Anne, Kuba, M. Gabriela, Ross, Dara, Giri, Dilip, Wen, Hannah Y., Zhang, Hong, Brogi, Edi, Weigelt, Britta, Pareja, Fresia, and Reis-Filho, Jorge S.

Published
2024
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3. Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses

Author

Friedman, Claire F., Manning-Geist, Beryl L., Zhou, Qin, Soumerai, Tara, Holland, Aliya, Da Cruz Paula, Arnaud, Green, Hunter, Ozsoy, Melih Arda, Iasonos, Alexia, Hollmann, Travis, Leitao, Jr., Mario M., Mueller, Jennifer J., Makker, Vicky, Tew, William P., O’Cearbhaill, Roisin E., Liu, Ying L., Rubinstein, Maria M., Troso-Sandoval, Tiffany, Lichtman, Stuart M., Schram, Alison, Kyi, Chrisann, Grisham, Rachel N., Causa Andrieu, Pamela, Wherry, E. John, Aghajanian, Carol, Weigelt, Britta, Hensley, Martee L., and Zamarin, Dmitriy

Published
2024
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4. Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer

Author

Gomez-Banoy, Nicolas, Ortiz, Eduardo J., Jiang, Caroline S., Dagher, Christian, Sevilla, Carlo, Girshman, Jeffrey, Pagano, Andrew M., Plodkowski, Andrew J., Zammarrelli, William A., Mueller, Jennifer J., Aghajanian, Carol, Weigelt, Britta, Makker, Vicky, Cohen, Paul, and Osorio, Juan C.

Subjects
Drug therapy, Physiological aspects, Dosage and administration, Health aspects, Endometrial cancer -- Physiological aspects -- Drug therapy, Body mass index -- Health aspects, Medical research, Adipose tissue -- Health aspects, Immune checkpoint inhibitors -- Physiological aspects -- Dosage and administration, Medicine, Experimental, Adipose tissues -- Health aspects
Abstract

Introduction Endometrial cancer (EC) constitutes the leading cause of gynecologic cancer-related death in the United States and one of the few cancer types with increasing incidence and disease-associated mortality (1). [...], BACKGROUND. Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association among BMI, body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI. METHODS. We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat-mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAEs) after ICI was also assessed based on BMI status. RESULTS. 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared with normal BMI patients after treatment with ICI. Multivariable Cox's regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared with normal BMI individuals. CONCLUSION. Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype. FUNDING. NIH/NCI Cancer Center; MSK Gerstner Physician Scholars Program; National Center for Advancing Translational Sciences (NCATS); Cycle for Survival; Breast Cancer Research Foundation.

Published
2024
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5. Epigenetic dysregulation from chromosomal transit in micronuclei.

Author

Agustinus, Albert S, Al-Rawi, Duaa, Dameracharla, Bhargavi, Raviram, Ramya, Jones, Bailey SCL, Stransky, Stephanie, Scipioni, Lorenzo, Luebeck, Jens, Di Bona, Melody, Norkunaite, Danguole, Myers, Robert M, Duran, Mercedes, Choi, Seongmin, Weigelt, Britta, Yomtoubian, Shira, McPherson, Andrew, Toufektchan, Eléonore, Keuper, Kristina, Mischel, Paul S, Mittal, Vivek, Shah, Sohrab P, Maciejowski, John, Storchova, Zuzana, Gratton, Enrico, Ly, Peter, Landau, Dan, Bakhoum, Mathieu F, Koche, Richard P, Sidoli, Simone, Bafna, Vineet, David, Yael, and Bakhoum, Samuel F

Subjects
Chromosomes, Chromatin, Animals, Humans, Mice, Neoplasms, Chromosomal Instability, Histones, Epigenesis, Genetic, Human Genome, Genetics, Cancer, General Science & Technology
Abstract

Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1-4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.

Published
2023

7. Molecular subclasses of clear cell ovarian carcinoma and their impact on disease behavior and outcomes

Author

Bolton, Kelly L, Chen, Denise, de la Fuente, Rosario I Corona, Fu, Zhuxuan, Murali, Rajmohan, K�bel, Martin, Tazi, Yanis, Cunningham, Julie M, Chan, Irenaeus CC, Wiley, Brian J, Moukarzel, Lea A, Winham, Stacey J, Armasu, Sebastian M, Lester, Jenny, Elishaev, Esther, Laslavic, Angela, Kennedy, Catherine J, Piskorz, Anna, Sekowska, Magdalena, Brand, Alison H, Chiew, Yoke-Eng, Pharoah, Paul, Elias, Kevin M, Drapkin, Ronny, Churchman, Michael, Gourley, Charlie, DeFazio, Anna, Karlan, Beth, Brenton, James D, Weigelt, Britta, Anglesio, Michael S, Huntsman, David, Gayther, Simon A, Konner, Jason, Modugno, Francesmary, Lawrenson, Kate, Goode, Ellen L, and Papaemmanuil, Elli

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Women's Health, Human Genome, Genetics, Rare Diseases, Cancer, Biotechnology, Cancer Genomics, Precision Medicine, Clinical Research, 2.1 Biological and endogenous factors, Good Health and Well Being, Female, Humans, Ovarian Neoplasms, Adenocarcinoma, Clear Cell, Mutation, Endometriosis, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeTo identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.Experimental designWe profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival.ResultsWe detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy.ConclusionsOur study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.

Published
2022

8. Basket study of oral progesterone antagonist onapristone extended release in progesterone receptor-positive recurrent granulosa cell, low-grade serous ovarian cancer, or endometrioid endometrial cancer

Author

Andres, Sarah, Finch, Lindsey, Iasonos, Alexia, Zhou, Qin, Girshman, Jeffrey, Chhetri-Long, Rashmi, Green, Hunter, Jang, Dasom, O'Cearbhaill, Roisin, Kyi, Chrisann, Cohen, Seth, Friedman, Claire, Makker, Vicky, Chi, Dennis S., Sonoda, Yukio, Chiang, Sarah, Aghajanian, Carol, Weigelt, Britta, and Grisham, Rachel N.

Published
2024
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9. Long-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers

Author

Setton, Jeremy, Hadi, Kevin, Choo, Zi-Ning, Kuchin, Katherine S., Tian, Huasong, Da Cruz Paula, Arnaud, Rosiene, Joel, Selenica, Pier, Behr, Julie, Yao, Xiaotong, Deshpande, Aditya, Sigouros, Michael, Manohar, Jyothi, Nauseef, Jones T., Mosquera, Juan-Miguel, Elemento, Olivier, Weigelt, Britta, Riaz, Nadeem, Reis-Filho, Jorge S., Powell, Simon N., and Imieliński, Marcin

Published
2023
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13. Mainstreaming in parallel with ovarian cancer tumor testing to improve genetic testing uptake

Author

Byrne, Maureen, Sia, Tiffany Y., Fong, Christopher, Khurram, Aliya, Waters, Michele, Kemel, Yelena M., Zhou, Qin, Ranganathan, Megha, Long Roche, Kara, Chi, Dennis S., Saban, Sally, Wu, Michelle, Varice, Nancy, Hamilton, Jada G., Carrot-Zhang, Jian, Abu-Rustum, Nadeem R., Iasonos, Alexia, Ellenson, Lora H., Mandelker, Diana, Weigelt, Britta, Brown, Carol L., Aghajanian, Carol, Stadler, Zsofia, and Liu, Ying L.

Published
2024
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15. Morphological and genomic characteristics of breast cancers occurring in individuals with Lynch Syndrome

Author

Schwartz, Christopher J, da Silva, Edaise M, Marra, Antonio, Gazzo, Andrea M, Selenica, Pier, Rai, Vikas K, Mandelker, Diana, Pareja, Fresia, Misyura, Maksym, D'Alfonso, Timothy M, Brogi, Edi, Drullinsky, Pamela, Razavi, Pedram, Robson, Mark E, Drago, Joshua Z, Wen, Hannah Y, Zhang, Liying, Weigelt, Britta, Shia, Jinru, Reis-Filho, Jorge S, and Zhang, Hong

Subjects
Colo-Rectal Cancer, Cancer, Breast Cancer, Rare Diseases, Digestive Diseases, Genetic Testing, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Breast Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, DNA Mismatch Repair, Female, Germ-Line Mutation, Humans, Microsatellite Instability, MutL Protein Homolog 1, Retrospective Studies, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeLynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and endometrial cancers. Whether breast cancers developing in the context of Lynch syndrome are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphologic and genomic characteristics of breast cancers occurring in Lynch syndrome individuals.Experimental designA retrospective analysis of 20,110 patients with cancer who underwent multigene panel genetic testing was performed to identify individuals with a likely pathogenic/pathogenic germline variant in MLH1, MSH2, MSH6, or PMS2 who developed breast cancers. The histologic characteristics and IHC assessment of breast cancers for MMR proteins and programmed death-ligand 1 (PD-L1) expression were assessed on cases with available materials. DNA samples from paired tumors and blood were sequenced with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (≥468 key cancer genes). Microsatellite instability (MSI) status was assessed utilizing MSISensor. Mutational signatures were defined using SigMA.ResultsA total of 272 individuals with Lynch syndrome were identified, 13 (5%) of whom had primary breast cancers. The majority of breast cancers (92%) were hormone receptor-positive tumors. Five (42%) of 12 breast cancers displayed loss of MMR proteins by IHC. Four (36%) of 11 breast cancers subjected to tumor-normal sequencing showed dominant MSI mutational signatures, high tumor mutational burden, and indeterminate (27%) or high MSISensor scores (9%). One patient with metastatic MMRd breast cancer received anti-PD1 therapy and achieved a robust and durable response.ConclusionsA subset of breast cancers developing in individuals with Lynch syndrome are etiologically linked to MMRd and may benefit from anti-PD1/PD-L1 immunotherapy.

Published
2022

16. Germline RAD51B variants confer susceptibility to breast and ovarian cancers deficient in homologous recombination.

Author

Setton, Jeremy, Selenica, Pier, Mukherjee, Semanti, Shah, Rachna, Pecorari, Isabella, McMillan, Biko, Pei, Isaac X, Kemel, Yelena, Ceyhan-Birsoy, Ozge, Sheehan, Margaret, Tkachuk, Kaitlyn, Brown, David N, Zhang, Liying, Cadoo, Karen, Powell, Simon, Weigelt, Britta, Robson, Mark, Riaz, Nadeem, Offit, Kenneth, Reis-Filho, Jorge S, and Mandelker, Diana

Subjects
Breast Cancer, Rare Diseases, Genetics, Cancer, Biotechnology, Ovarian Cancer, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies
Abstract

Pathogenic germline mutations in the RAD51 paralog genes RAD51C and RAD51D, are known to confer susceptibility to ovarian and triple-negative breast cancer. Here, we investigated whether germline loss-of-function variants affecting another RAD51 paralog gene, RAD51B, are also associated with breast and ovarian cancer. Among 3422 consecutively accrued breast and ovarian cancer patients consented to tumor/germline sequencing, the observed carrier frequency of loss-of-function germline RAD51B variants was significantly higher than control cases from the gnomAD population database (0.26% vs 0.09%), with an odds ratio of 2.69 (95% CI: 1.4-5.3). Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.

Published
2021

17. Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer

Author

De Angelis, Carmine, Fu, Xiaoyong, Cataldo, Maria Letizia, Nardone, Agostina, Pereira, Resel, Veeraraghavan, Jamunarani, Nanda, Sarmistha, Qin, Lanfang, Sethunath, Vidyalakshmi, Wang, Tao, Hilsenbeck, Susan G, Benelli, Matteo, Migliaccio, Ilenia, Guarducci, Cristina, Malorni, Luca, Litchfield, Lacey M, Liu, Jiangang, Donaldson, Joshua, Selenica, Pier, Brown, David N, Weigelt, Britta, Reis-Filho, Jorge S, Park, Ben H, Hurvitz, Sara A, Slamon, Dennis J, Rimawi, Mothaffar F, Jansen, Valerie M, Jeselsohn, Rinath, Osborne, C Kent, and Schiff, Rachel

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Genetics, Breast Cancer, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Good Health and Well Being, Antineoplastic Agents, Breast Neoplasms, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Female, Humans, Piperazines, Pyridines, Receptors, Estrogen, Signal Transduction, Tumor Cells, Cultured, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeCyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor-positive (ER+)/HER2- breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes.Experimental designParental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes.ResultsParental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an "IFN-related palbociclib-resistance Signature" (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis.ConclusionsAberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.

Published
2021

18. Nonlobular Invasive Breast Carcinomas with Biallelic Pathogenic CDH1 Somatic Alterations: A Histologic, Immunophenotypic, and Genomic Characterization

Author

Derakhshan, Fatemeh, Da Cruz Paula, Arnaud, Selenica, Pier, da Silva, Edaise M., Grabenstetter, Anne, Jalali, Sahar, Gazzo, Andrea M., Dopeso, Higinio, Marra, Antonio, Brown, David N., Ross, Dara S., Mandelker, Diana, Razavi, Pedram, Chandarlapaty, Sarat, Wen, Hannah Y., Brogi, Edi, Zhang, Hong, Weigelt, Britta, Pareja, Fresia, and Reis-Filho, Jorge S.

Published
2024
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19. Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion

Author

Kudo, Rei, Safonov, Anton, Jones, Catherine, Moiso, Enrico, Dry, Jonathan R., Shao, Hong, Nag, Sharanya, da Silva, Edaise M., Yildirim, Selma Yeni, Li, Qing, O'Connell, Elizabeth, Patel, Payal, Will, Marie, Fushimi, Atsushi, Benitez, Marimar, Bradic, Martina, Fan, Li, Nakshatri, Harikrishna, Sudhan, Dhivya R., Denz, Christopher R., Huerga Sanchez, Iker, Reis-Filho, Jorge S., Goel, Shom, Koff, Andrew, Weigelt, Britta, Khan, Qamar J., Razavi, Pedram, and Chandarlapaty, Sarat

Published
2024
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20. Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival

Author

Kahn, Ryan M., Selenica, Pier, Boerner, Thomas, Long Roche, Kara, Xiao, Yonghong, Sia, Tiffany Y., Maio, Anna, Kemel, Yelena, Sheehan, Margaret, Salo-Mullen, Erin, Breen, Kelsey E., Zhou, Qin, Iasonos, Alexia, Grisham, Rachel N., O’Cearbhaill, Roisin E., Chi, Dennis S., Berger, Michael F., Kundra, Ritika, Schultz, Nikolaus, Ellenson, Lora H., Stadler, Zsofia K., Offit, Kenneth, Mandelker, Diana, Aghajanian, Carol, Zamarin, Dmitriy, Sabbatini, Paul, Weigelt, Britta, and Liu, Ying L.

Published
2024
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24. HER2 Genetic Intratumor Heterogeneity Is Associated With Resistance to Trastuzumab and Trastuzumab Emtansine Therapy in Recurrent High-Grade Endometrial Cancer

Author

Shen, Sherry, Ma, Weining, Brown, David, Da Cruz Paula, Arnaud, Zhou, Qin, Iaosonos, Alexia, Tessier-Cloutier, Basile, Ross, Dara S., Troso-Sandoval, Tiffany, Reis-Filho, Jorge S., Abu-Rustum, Nadeem, Zhang, Yanming, Ellenson, Lora H., Weigelt, Britta, Makker, Vicky, and Chui, M. Herman

Published
2023
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25. Ovarian cancer mutational processes drive site-specific immune evasion

Author

Vázquez-García, Ignacio, Uhlitz, Florian, Ceglia, Nicholas, Lim, Jamie L. P., Wu, Michelle, Mohibullah, Neeman, Niyazov, Juliana, Ruiz, Arvin Eric B., Boehm, Kevin M., Bojilova, Viktoria, Fong, Christopher J., Funnell, Tyler, Grewal, Diljot, Havasov, Eliyahu, Leung, Samantha, Pasha, Arfath, Patel, Druv M., Pourmaleki, Maryam, Rusk, Nicole, Shi, Hongyu, Vanguri, Rami, Williams, Marc J., Zhang, Allen W., Broach, Vance, Chi, Dennis S., Da Cruz Paula, Arnaud, Gardner, Ginger J., Kim, Sarah H., Lennon, Matthew, Long Roche, Kara, Sonoda, Yukio, Zivanovic, Oliver, Kundra, Ritika, Viale, Agnes, Derakhshan, Fatemeh N., Geneslaw, Luke, Issa Bhaloo, Shirin, Maroldi, Ana, Nunez, Rahelly, Pareja, Fresia, Stylianou, Anthe, Vahdatinia, Mahsa, Bykov, Yonina, Grisham, Rachel N., Liu, Ying L., Lakhman, Yulia, Nikolovski, Ines, Kelly, Daniel, Gao, Jianjiong, Schietinger, Andrea, Hollmann, Travis J., Bakhoum, Samuel F., Soslow, Robert A., Ellenson, Lora H., Abu-Rustum, Nadeem R., Aghajanian, Carol, Friedman, Claire F., McPherson, Andrew, Weigelt, Britta, Zamarin, Dmitriy, and Shah, Sohrab P.

Published
2022
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26. Single-cell genomic variation induced by mutational processes in cancer

Author

Funnell, Tyler, O’Flanagan, Ciara H., Williams, Marc J., McPherson, Andrew, McKinney, Steven, Kabeer, Farhia, Lee, Hakwoo, Salehi, Sohrab, Vázquez-García, Ignacio, Shi, Hongyu, Leventhal, Emily, Masud, Tehmina, Eirew, Peter, Yap, Damian, Zhang, Allen W., Lim, Jamie L. P., Wang, Beixi, Brimhall, Jazmine, Biele, Justina, Ting, Jerome, Au, Vinci, Van Vliet, Michael, Liu, Yi Fei, Beatty, Sean, Lai, Daniel, Pham, Jenifer, Grewal, Diljot, Abrams, Douglas, Havasov, Eliyahu, Leung, Samantha, Bojilova, Viktoria, Moore, Richard A., Rusk, Nicole, Uhlitz, Florian, Ceglia, Nicholas, Weiner, Adam C., Zaikova, Elena, Douglas, J. Maxwell, Zamarin, Dmitriy, Weigelt, Britta, Kim, Sarah H., Da Cruz Paula, Arnaud, Reis-Filho, Jorge S., Martin, Spencer D., Li, Yangguang, Xu, Hong, de Algara, Teresa Ruiz, Lee, So Ra, Llanos, Viviana Cerda, Huntsman, David G., McAlpine, Jessica N., Shah, Sohrab P., and Aparicio, Samuel

Published
2022
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27. Integration of clinical sequencing and immunohistochemistry for the molecular classification of endometrial carcinoma

Author

Rios-Doria, Eric, Momeni-Boroujeni, Amir, Friedman, Claire F., Selenica, Pier, Zhou, Qin, Wu, Michelle, Marra, Antonio, Leitao, Mario M., Jr, Iasonos, Alexia, Alektiar, Kaled M., Sonoda, Yukio, Makker, Vicky, Jewell, Elizabeth, Liu, Ying, Chi, Dennis, Zamarin, Dimitry, Abu-Rustum, Nadeem R., Aghajanian, Carol, Mueller, Jennifer J., Ellenson, Lora H., and Weigelt, Britta

Published
2023
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28. Germline drivers of gynecologic carcinosarcomas

Author

Sia, Tiffany Y., Gordhandas, Sushmita B., Birsoy, Ozge, Kemel, Yelena, Maio, Anna, Salo-Mullen, Erin, Sheehan, Margaret, Hensley, Martee L., Rubinstein, Maria, Makker, Vicky, Grisham, Rachel N., O’Cearbhaill, Roisin E., Long Roche, Kara, Mueller, Jennifer J., Leitao, Mario M., Jr, Sonoda, Yukio, Chi, Dennis S., Abu-Rustum, Nadeem R., Berger, Michael F., Ellenson, Lora H., Latham, Alicia, Stadler, Zsofia, Offit, Kenneth, Aghajanian, Carol, Weigelt, Britta, Mandelker, Diana, and Liu, Ying L.

Published
2023
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29. Immunohistochemical analysis of IDH2 R172 hotspot mutations in breast papillary neoplasms: applications in the diagnosis of tall cell carcinoma with reverse polarity

Author

Pareja, Fresia, da Silva, Edaise M, Frosina, Denise, Geyer, Felipe C, Lozada, John R, Basili, Thais, Da Cruz Paula, Arnaud, Zhong, Elaine, Derakhshan, Fatemeh, D’Alfonso, Timothy, Wen, Hannah Y, Giri, Dilip D, Hayes, Malcolm M, Krings, Gregor, Bhargava, Rohit, Palazzo, Juan P, Rakha, Emad A, Hoda, Syed A, Sanders, Melinda E, Collins, Laura C, Schnitt, Stuart J, Chen, Yunn-Yi, Weigelt, Britta, Jungbluth, Achim A, Reis-Filho, Jorge S, and Brogi, Edi

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Biotechnology, Aged, Aged, 80 and over, Biomarkers, Tumor, Breast Neoplasms, Carcinoma, Papillary, Cell Polarity, Female, Humans, Immunohistochemistry, Isocitrate Dehydrogenase, Middle Aged, Mutation, Medical and Health Sciences, Pathology, Clinical sciences
Abstract

Tall cell carcinoma with reverse polarity is a rare subtype of breast carcinoma with solid and papillary growth and nuclear features reminiscent of those of the tall cell variant of papillary thyroid carcinoma. These tumors harbor recurrent IDH2 R172 hotspot mutations or TET2 mutations, co-occurring with mutations in PI3K pathway genes. Diagnosis of tall cell carcinomas with reverse polarity is challenging in view of their rarity and the range of differential diagnosis. We sought to determine the sensitivity and specificity of IDH2 R172 immunohistochemistry for the detection of IDH2 R172 hotspot mutations in this entity. We evaluated 14 tall cell carcinomas with reverse polarity (ten excision and five core needle biopsy specimens), 13 intraductal papillomas, 16 solid papillary carcinomas, and 5 encapsulated papillary carcinomas by Sanger sequencing of the IDH2 R172 hotspot locus and of exons 9 and 20 of PIK3CA, and by immunohistochemistry using monoclonal antibodies (11C8B1) to the IDH2 R172S mutation. The 14 tall cell carcinomas with reverse polarity studied harbored IDH2 R172 hotspot mutations, which co-occurred with PIK3CA hotspot mutations in 50% of cases. None of the other papillary neoplasms analyzed displayed IDH2 R172 mutations, however PIK3CA hotspot mutations were detected in 54% of intraductal papillomas, 6% of solid papillary carcinomas, and 20% of encapsulated papillary carcinomas tested. Immunohistochemical analysis with anti-IDH2 R172S antibodies (11C8B1) detected IDH2 R172 mutated protein in 93% (14/15) of tall cell carcinomas with reverse polarity samples including excision (n = 9/10) and core needle biopsy specimens (n = 5), whereas the remaining papillary neoplasms (n = 34) were negative. Our findings demonstrate that immunohistochemical analysis of IDH2 R172 is highly sensitive and specific for the detection of IDH2 R172 hotspot mutations, and likely suitable as a diagnostic tool in the evaluation of excision and core needle biopsy material of tall cell carcinomas with reverse polarity.

Published
2020

36. Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer

Author

Gomez-Banoy, Nicolas, primary, Ortiz, Eduardo J, additional, Jiang, Caroline S., additional, Dagher, Christian, additional, Sevilla, Carlo, additional, Girshman, Jeffrey, additional, Pagano, Andrew, additional, Plodkowski, Andrew J, additional, Zammarrelli, William, additional, Mueller, Jennifer J., additional, Aghajanian, Carol, additional, Weigelt, Britta, additional, Makker, Vicky, additional, Cohen, Paul, additional, and Osorio, Juan C, additional

Published
2024
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37. A phase II study of fulvestrant and abemaciclib in hormone receptor positive advanced or recurrent endometrial cancer.

Author

Green, Angela, primary, Zhou, Qin, additional, Iasonos, Alexia, additional, Zammarrelli, William, additional, Weigelt, Britta, additional, Ellenson, Lora H, additional, Chhetri-Long, Rashmi, additional, Shah, Pooja, additional, Hom, Vania, additional, Erinjeri, Joseph P., additional, Petkovska, Iva, additional, Chandarlapaty, Sarat, additional, Cohen, Seth M., additional, Grisham, Rachel N., additional, Konner, Jason A., additional, Rubinstein, Maria M, additional, Tew, William P., additional, Troso-Sandoval, Tiffany A., additional, Aghajanian, Carol, additional, and Makker, Vicky, additional

Published
2024
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38. The combination of patient-specific tumor and HPV sequencing to enable high-sensitivity detection of ctDNA in patients with HPV-associated oropharyngeal carcinoma.

Author

Diplas, Bill, primary, Brown, David N, additional, Pei, Xin, additional, Chen, Linda, additional, Graybill, Chiharu, additional, Korn, W. Michael, additional, Westheimer, Emily, additional, Novaj, Ardijana, additional, Humm, John, additional, Shukla-Dave, Amita, additional, Schöder, Heiko, additional, Katabi, Nora, additional, Sherman, Eric Jeffrey, additional, Reis-Filho, Jorge, additional, Weigelt, Britta, additional, LEE, NANCY Y., additional, and Riaz, Nadeem, additional

Published
2024
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39. TBCRC 058: A randomized phase II study of enzalutamide, enzalutamide with mifepristone, and treatment of physician’s choice in patients with androgen receptor-positive metastatic triple-negative or estrogen receptor-low breast cancer (NCT06099769).

Author

Traina, Tiffany A., primary, Chen, Yuan, additional, Khoury, Katia, additional, Rugo, Hope S., additional, Mayer, Erica L., additional, Carey, Lisa A., additional, Melisko, Michelle E., additional, Syldor, Angemael, additional, Friedman, Chaya, additional, Savoie, Jennifer, additional, Pareja, Fresia, additional, Weigelt, Britta, additional, Chandarlapaty, Sarat, additional, Turner, Nicholas C., additional, Conzen, Suzanne D., additional, and Nanda, Rita, additional

Published
2024
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40. Molecular profiling of primary endometroid endometrial cancer and matched lung metastases: CTNNB1 mutation as a potential driver

Author

Gordhandas, Sushmita, primary, Da Cruz Paula, Arnaud, additional, Kertowidjojo, Elizabeth C., additional, Pareja, Fresia, additional, Dessources, Kimberly, additional, da Silva, Edaise M., additional, Derakhshan, Fatemeh, additional, Mueller, Jennifer J., additional, Abu-Rustum, Nadeem R., additional, Herman Chui, M., additional, and Weigelt, Britta, additional

Published
2024
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44. Fundamental immune–oncogenicity trade-offs define driver mutation fitness

Author

Hoyos, David, Zappasodi, Roberta, Schulze, Isabell, Sethna, Zachary, de Andrade, Kelvin César, Bajorin, Dean F., Bandlamudi, Chaitanya, Callahan, Margaret K., Funt, Samuel A., Hadrup, Sine R., Holm, Jeppe S., Rosenberg, Jonathan E., Shah, Sohrab P., Vázquez-García, Ignacio, Weigelt, Britta, Wu, Michelle, Zamarin, Dmitriy, Campitelli, Laura F., Osborne, Edward J., Klinger, Mark, Robins, Harlan S., Khincha, Payal P., Savage, Sharon A., Balachandran, Vinod P., Wolchok, Jedd D., Hellmann, Matthew D., Merghoub, Taha, Levine, Arnold J., Łuksza, Marta, and Greenbaum, Benjamin D.

Published
2022
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45. Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma

Author

Ho, Allen S, Ochoa, Angelica, Jayakumaran, Gowtham, Zehir, Ahmet, Mayor, Cristina Valero, Tepe, Justin, Makarov, Vladimir, Dalin, Martin G, He, Jie, Bailey, Mark, Montesion, Meagan, Ross, Jeffrey S, Miller, Vincent A, Chan, Lindsay, Ganly, Ian, Dogan, Snjezana, Katabi, Nora, Tsipouras, Petros, Ha, Patrick, Agrawal, Nishant, Solit, David B, Futreal, P Andrew, Naggar, Adel K El, Reis-Filho, Jorge S, Weigelt, Britta, Ho, Alan L, Schultz, Nikolaus, Chan, Timothy A, and Morris, Luc GT

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Cancer, Clinical Research, Digestive Diseases, Good Health and Well Being, Adult, Carcinoma, Adenoid Cystic, Chromatin Assembly and Disassembly, Female, Genes, myb, Genomics, Humans, Male, Middle Aged, Mutation, Neoplasm Recurrence, Local, Receptors, Notch, Salivary Gland Neoplasms, Telomerase, Head and neck cancer, Oncology, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BACKGROUNDAdenoid cystic carcinoma (ACC) is a rare malignancy arising in salivary glands and other sites, characterized by high rates of relapse and distant spread. Recurrent/metastatic (R/M) ACCs are generally incurable, due to a lack of active systemic therapies. To improve outcomes, deeper understanding of genetic alterations and vulnerabilities in R/M tumors is needed.METHODSAn integrated genomic analysis of 1,045 ACCs (177 primary, 868 R/M) was performed to identify alterations associated with advanced and metastatic tumors. Intratumoral genetic heterogeneity, germline mutations, and therapeutic actionability were assessed.RESULTSCompared with primary tumors, R/M tumors were enriched for alterations in key Notch (NOTCH1, 26.3% vs. 8.5%; NOTCH2, 4.6% vs. 2.3%; NOTCH3, 5.7% vs. 2.3%; NOTCH4, 3.6% vs. 0.6%) and chromatin-remodeling (KDM6A, 15.2% vs. 3.4%; KMT2C/MLL3, 14.3% vs. 4.0%; ARID1B, 14.1% vs. 4.0%) genes. TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 × 10-3), suggesting discrete, alternative mechanisms of tumorigenesis. This network of alterations defined 4 distinct ACC subgroups: MYB+NOTCH1+, MYB+/other, MYBWTNOTCH1+, and MYBWTTERT+. Despite low mutational load, we identified numerous samples with marked intratumoral genetic heterogeneity, including branching evolution across multiregion sequencing.CONCLUSIONThese observations collectively redefine the molecular underpinnings of ACC progression and identify further targets for precision therapies.FUNDINGAdenoid Cystic Carcinoma Research Foundation, Pershing Square Sohn Cancer Research grant, the PaineWebber Chair, Stand Up 2 Cancer, NIH R01 CA205426, the STARR Cancer Consortium, NCI R35 CA232097, the Frederick Adler Chair, Cycle for Survival, the Jayme Flowers Fund, The Sebastian Nativo Fund, NIH K08 DE024774 and R01 DE027738, and MSKCC through NIH/NCI Cancer Center Support Grant (P30 CA008748).

Published
2019

46. Long-term Outcomes of Local and Metastatic Small Cell Carcinoma of the Urinary Bladder and Genomic Analysis of Patients Treated With Neoadjuvant Chemotherapy

Author

Teo, Min Yuen, Guercio, Brendan J., Arora, Arshi, Hao, Xueli, Regazzi, Ashley M., Donahue, Timothy, Herr, Harry W., Goh, Alvin C., Cha, Eugene K., Pietzak, Eugene, Donat, Sherri M., Dalbagni, Guido, Bochner, Bernard H., Olgac, Semra, Sarungbam, Judy, Sirintrapun, S. Joseph, Chen, Ying-Bei, Gopalan, Anuradha, Fine, Samson W., Tickoo, Satish K., Reuter, Victor E., Weigelt, Britta, Schultheis, Anne M., Funt, Samuel A., Bajorin, Dean F., Solit, David B., Iyer, Gopa, Ostrovnaya, Irina, Rosenberg, Jonathan E., and Al-Ahmadie, Hikmat

Published
2022
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47. Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA

Author

Chandran, Smita S., Ma, Jiaqi, Klatt, Martin G., Dündar, Friederike, Bandlamudi, Chaitanya, Razavi, Pedram, Wen, Hannah Y., Weigelt, Britta, Zumbo, Paul, Fu, Si Ning, Banks, Lauren B., Yi, Fei, Vercher, Enric, Etxeberria, Inaki, Bestman, Watchain D., Da Cruz Paula, Arnaud, Aricescu, Ilinca S., Drilon, Alexander, Betel, Doron, Scheinberg, David A., Baker, Brian M., and Klebanoff, Christopher A.

Published
2022
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49. Intratumor genetic heterogeneity and clonal evolution to decode endometrial cancer progression

Author

Mota, Alba, Oltra, Sara S., Selenica, Pier, Moiola, Cristian P., Casas-Arozamena, Carlos, López-Gil, Carlos, Diaz, Eva, Gatius, Sonia, Ruiz-Miro, María, Calvo, Ana, Rojo-Sebastián, Alejandro, Hurtado, Pablo, Piñeiro, Roberto, Colas, Eva, Gil-Moreno, Antonio, Reis-Filho, Jorge S., Muinelo-Romay, Laura, Abal, Miguel, Matias-Guiu, Xavier, Weigelt, Britta, and Moreno-Bueno, Gema

Published
2022
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50. ERBB2 mutations define a subgroup of endometrial carcinomas associated with high tumor mutational burden and the microsatellite instability‐high (MSI‐H) molecular subtype.

Author

Brodeur, Melica Nourmoussavi, Selenica, Pier, Ma, Weining, Moufarrij, Sara, Dagher, Christian, Basili, Thais, Abu‐Rustum, Nadeem R., Aghajanian, Carol, Zhou, Qin, Iasonos, Alexia, Ellenson, Lora H., Weigelt, Britta, and Chui, M. Herman

Abstract

Anti‐HER2 therapy is indicated for erb‐b2 receptor tyrosine kinase 2 (ERBB2)‐amplified/overexpressing endometrial carcinoma (EC). Mutations constitute another mode of ERBB2 activation, but only rare ERBB2‐mutated ECs have been reported. We sought to characterize the clinicopathologic and genetic features of ERBB2‐mutated EC. From an institutional cohort of 2638 ECs subjected to clinical tumor‐normal panel sequencing, 69 (2.6%) with pathogenic ERBB2 mutation(s) were identified, of which 11 were also ERBB2‐amplified. The most frequent ERBB2 hotspot mutations were V842I (38%) and R678Q (25%). ERBB2 mutations were clonal in 87% of evaluable cases. Immunohistochemistry revealed low HER2 protein expression in most ERBB2‐mutated ECs (0/1+ in 66%, 2+ in 27%); all 3+ tumors (7.3%) were also ERBB2‐amplified. Compared to ERBB2‐wildtype ECs (with or without ERBB2 amplification), ERBB2‐mutated/non‐amplified ECs were enriched for the microsatellite instability‐high (MSI‐H) and, to a lesser extent, DNA polymerase epsilon, catalytic subunit (POLE) molecular subtypes, and associated with high tumor mutational burden and low chromosomal instability. Survival outcomes were similar between patients with ERBB2‐mutated/non‐amplified versus wildtype EC, whereas ERBB2 amplification was associated with worse prognosis on univariate, but not multivariate, analyses. In conclusion, ERBB2 mutation defines a rare subgroup of ECs that is pathogenically distinct from ERBB2‐wildtype and ERBB2‐amplified ECs. [ABSTRACT FROM AUTHOR]

Published
2024
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