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Francesca Vena, Ruochen Jia, Arman Esfandiari, Juan J Garcia-Gomez, Manuel Rodriguez-Justo, Jianguo Ma, Sakeena Syed, Lindsey Crowley, Brian Elenbaas, Samantha Goodstal, John A Hartley, Daniel Hochhauser
Targeting the DNA damage response (DDR) in tumors with defective DNA repair is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is frequently deregulated in human cancers. In this study, we explored the effects of MEK inhibition on the homologous recombination pathway and explored the potential for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated prodrug. We studied effects of combining pimasertib, a selective allosteric inhibitor of MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug evofosfamide in ovarian and pancreatic cancer cell lines...
February 20, 2018: Oncotarget
(no author information available yet)
The FDA authorized 23andMe to market the first direct-to-consumer test to check for three BRCA1/2 mutations associated with a higher risk of developing breast, ovarian, and prostate cancers. The mutations are most commonly found in about 2% of women of Ashkenazi Jewish descent.
March 14, 2018: Cancer Discovery
Susana Cedrés, Enriqueta Felip, Cristina Cruz, Ana Martinez de Castro, Nuria Pardo, Alejandro Navarro, Alex Martinez-Marti, Jordin Remon, Jorge Zeron-Medina, Judith Balmaña, Alba Llop-Guevara, Josep M Miquel, Irene Sansano, Paolo Nuciforo, Francesco Mancuso, Violeta Serra, Ana Vivancos
Heat shock proteins (HSPs) are molecular chaperones that maintain proteins in their correct conformation to ensure stability and protect carcinoma cells from apoptosis. HSP90 inhibitors (HSP90i) block multiple targets simultaneously, and despite responses in a selected population, no HSP90i have yet been approved. We present a patient with a lung tumor with an exceptional response to cisplatin/gemcitabine in combination with HSP90i, which nowadays continues with HSP90i maintenance after three years. Whole-exome sequencing of the lung tumor unveiled a BRCA1/2 deficiency mutational signature, and mutation analysis confirmed a germline BRCA1 mutation...
February 26, 2018: Journal of the National Cancer Institute
Akiyo Yoshimura, Seiko Okumura, Masataka Sawaki, Masaya Hattori, Junko Ishiguro, Yayoi Adachi, Haruru Kotani, Naomi Gondo, Ayumi Kataoka, Madoka Iwase, Sakura Onishi, Kayoko Sugino, Mitsuo Terada, Nanae Horisawa, Makiko Mori, Nobue Takaiso, Ikuo Hyodo, Hiroji Iwata
BACKGROUND: Contralateral risk-reducing mastectomy (CRRM) for breast cancer patients with BRCA mutations has been reported to not only reduce breast cancer incidence but also to improve survival. The National Comprehensive Cancer Network guidelines recommend providing CRRM to women with BRCA mutations who desire CRRM after risk-reduction counseling. However, in Japan, CRRM cannot be performed generally because it is not covered by health insurance. Thus, we conducted a feasibility study to confirm the safety of CRRM...
March 8, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
Qi Liu, Liliana Gheorghiu, Michael Drumm, Rebecca Clayman, Alec Eidelman, Matthew F Wszolek, Aria Olumi, Adam Feldman, Meng Wang, Lynnette Marcar, Deborah E Citrin, Chin-Lee Wu, Cyril H Benes, Jason A Efstathiou, Henning Willers
Biomarkers and mechanisms of poly (ADP-ribose) polymerase (PARP) inhibitor-mediated cytotoxicity in tumor cells lacking a BRCA-mutant or BRCA-like phenotype are poorly defined. We sought to explore the utility of PARP-1 inhibitor (PARPi) treatment with/without ionizing radiation in muscle-invasive bladder cancer (MIBC), which has poor therapeutic outcomes. We assessed the DNA damaging and cytotoxic effects of the PARPi olaparib in nine bladder cancer cell lines. Olaparib radiosensitized all cell lines with dose enhancement factors from 1...
March 7, 2018: Oncogene
Sara Câmara, Daniela Pereira, Saudade André, Beatriz Mira, Fátima Vaz, Rodrigo Oom, José Carlos Marques, João Leal de Faria, Catarina Rodrigues Dos Santos
Introduction: Sentinel lymph node biopsy in prophylactic mastectomy is controversial. It avoids lymphadenectomy in occult carcinoma but is associated with increased morbidity. Women with BRCA mutations have a higher incidence of occult carcinoma and our objective was to assess the clinical utility of sentinel lymph node biopsy when these women undergo prophylactic mastectomy. Materials and Methods: Seven-year retrospective consecutive case-series study of women, with a BRCA deleterious mutation, admitted to prophylactic mastectomy, at our center...
2018: International Journal of Breast Cancer
Gillian E Hanley, Jessica N McAlpine, Dianne Miller, David Huntsman, Kasmintan A Schrader, C Blake Gilks, Gillian Mitchell
BACKGROUND: Identifying female carriers of BRCA1 and BRCA2 mutations is imperative for prevention of ovarian cancer and breast cancer. There are five major histologic subtypes of ovarian cancer and high grade serous cancer (the most common) is reported in 75-100% of BRCA1 and BRCA2 mutation carriers. We examined histology-based referral to the Hereditary Cancer Program following an educational prevention campaign recommending BRCA1 and BRCA2 mutation screening for all high-grade serous cancer patients...
March 5, 2018: BMC Cancer
Deyin Xing, Gang Zheng, John Kenneth Schoolmeester, Zaibo Li, Aparna Pallavajjala, Lisa Haley, Michael G Conner, Russell Vang, Chien-Fu Hung, Tzyy-Choou Wu, Brigitte M Ronnett
Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel...
March 2, 2018: American Journal of Surgical Pathology
Sibylle Loibl, Joyce O'Shaughnessy, Michael Untch, William M Sikov, Hope S Rugo, Mark D McKee, Jens Huober, Mehra Golshan, Gunter von Minckwitz, David Maag, Danielle Sullivan, Norman Wolmark, Kristi McIntyre, Jose J Ponce Lorenzo, Otto Metzger Filho, Priya Rastogi, W Fraser Symmans, Xuan Liu, Charles E Geyer
BACKGROUND: Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer...
February 28, 2018: Lancet Oncology
Siddhartha Yadav, Sruthi Jinna, Otavio Pereira-Rodrigues, Ashley Reeves, Sarah Campian, Amy Sufka, Dana Zakalik
The utility and benefit of integrating germ-line genetic testing into the management of newly diagnosed breast cancer is not fully understood. This study evaluates the impact of preoperative genetic testing on surgical decision making in patients with newly diagnosed breast cancer. Women with newly diagnosed breast cancer were classified into preoperative or postoperative genetic testing group, depending on whether they received their genetic testing results prior to or after their first surgery. Demographics, tumor characteristics, surgical treatment, and results of genetic testing were retrospectively collected...
March 2, 2018: Breast Journal
Emmet J Jordan, Maeve A Lowery, Olca Basturk, Peter J Allen, Kenneth H Yu, Viviane Tabar, Kathryn Beal, Diane L Reidy, Yoshiya Yamada, Yelena Janjigian, Ghassan K Abou-Alfa, Eileen M O'Reilly
PURPOSE: To assess clinical characteristics of patients with metastatic pancreas ductal adenocarcinoma (PDAC) and brain metastases (BM), and to assess somatic and germ-line molecular profiles where performed. PATIENTS AND METHODS: Patients with PDAC and BM between January 1990 and January 2016 were identified. Molecular characteristics of somatic and germ-line testing where performed in the subset of patients who had provided informed consent. Somatic alterations were assessed by either MSK-IMPACT testing (>340 key cancer genes) or Sequenom testing (8-gene panel)...
February 7, 2018: Clinical Colorectal Cancer
Ava Kwong, John C W Ho, Vivian Y Shin, Allison W Kurian, Edmund Tai, Laura J Esserman, Jeffery N Weitzel, Po-Han Lin, Michael Field, Susan M Domchek, Jessica Lo, Hextan Y S Ngan, Edmond S K Ma, Tsun L Chan, James M Ford
BRCA1/2 mutations are significant risk factors for hereditary breast and ovarian cancer (HBOC), its mutation frequency in HBOC of Chinese ethnicity is around 9%, in which nearly half are recurrent mutations. In Hong Kong and China, genetic testing and counseling are not as common as in the West. To reduce the barrier of testing, a multiplex SNaPshot genotyping panel that targeted 25 Chinese BRCA1/2 mutation hotspots was developed, and its feasibility was evaluated in a local cohort of 441 breast and 155 ovarian cancer patients...
January 30, 2018: Oncotarget
Serena Wong, Elena Ratner, Natalia Buza
AIMS: Prophylactic total hysterectomy (TH) and bilateral salpingo-oophorectomy (BSO) have become routine procedures in women at genetic risk for gynecologic malignancies. Intraoperative pathology diagnosis of an occult malignancy provides the opportunity for immediate surgical staging and helps avoiding a second surgery. However, no standard guidelines exist for optimal intraoperative evaluation (IOE) of these specimens. We performed a retrospective analysis of prophylactic TH and BSO cases to assess the presence of gross findings, frozen and permanent section sampling practices, frozen section diagnoses and diagnostic discrepancies...
February 26, 2018: Histopathology
Philip J Coates, Rudolf Nenutil, Jitka Holcakova, Marta Nekulova, Jan Podhorec, Marek Svoboda, Borivoj Vojtesek
The TP63 gene encodes two major protein variants that differ in their N-terminal sequences and have opposing effects. In breast, ΔNp63 is expressed by immature stem/progenitor cells and mature myoepithelial/basal cells and is a characteristic feature of basal-like triple-negative breast cancers (TNBCs). The expression and potential role of TAp63 in the mammary gland and breast cancers is less clear, partly due to the lack of studies that employ p63 isoform-specific antibodies. We used immunohistochemistry with ΔNp63-specific or TAp63-specific monoclonal antibodies to investigate p63 isoforms in 236 TNBCs...
February 27, 2018: Virchows Archiv: An International Journal of Pathology
Yize Mao, Xin Huang, Zeyu Shuang, Guohe Lin, Jun Wang, Fangting Duan, Jianlin Chen, Shengping Li
Cholangiocarcinoma (CCA) is a highly malignant tumor with resistance to radiotherapy alone. Olaparib, a highly potent poly(ADP-ribose) polymerase (PARP) inhibitor, has been shown to sensitize many types of tumor to radiotherapy. However, the effect of olaparib, either as monotherapy or as combination therapy with radiotherapy, on CCA is not known, and our study aimed to explore this. To assess radiosensitization in three CCA cell lines (QBC939, HuH28 and TFK-1), viability and clonogenic assays were conducted...
February 26, 2018: Cancer Medicine
Amanda Ewart Toland, Andrea Forman, Fergus J Couch, Julie O Culver, Diana M Eccles, William D Foulkes, Frans B L Hogervorst, Claude Houdayer, Ephrat Levy-Lahad, Alvaro N Monteiro, Susan L Neuhausen, Sharon E Plon, Shyam K Sharan, Amanda B Spurdle, Csilla Szabo, Lawrence C Brody
Clinical testing of BRCA1 and BRCA2 began over 20 years ago. With the expiration and overturning of the BRCA patents, limitations on which laboratories could offer commercial testing were lifted. These legal changes occurred approximately the same time as the widespread adoption of massively parallel sequencing (MPS) technologies. Little is known about how these changes impacted laboratory practices for detecting genetic alterations in hereditary breast and ovarian cancer genes. Therefore, we sought to examine current laboratory genetic testing practices for BRCA1 / BRCA2 ...
2018: NPJ Genomic Medicine
Jaya Singh, Nishita Thota, Suhasini Singh, Shila Padhi, Puja Mohan, Shivani Deshwal, Soumit Sur, Mithua Ghosh, Amit Agarwal, Ramesh Sarin, Rosina Ahmed, Sachin Almel, Basumita Chakraborti, Vinod Raina, Praveen K DadiReddy, B K Smruti, Senthil Rajappa, Chandragouda Dodagoudar, Shyam Aggarwal, Manish Singhal, Ashish Joshi, Rajeev Kumar, Ajai Kumar, Deepak K Mishra, Neeraj Arora, Aarati Karaba, Satish Sankaran, Shanmukh Katragadda, Arunabha Ghosh, Vamsi Veeramachaneni, Ramesh Hariharan, Ashraf U Mannan
PURPOSE: Breast and/or ovarian cancers are among the most common cancers in women across the world. In the Indian population, the healthcare burden of breast and/or ovarian cancers has been steadily rising, thus stressing the need for early detection, surveillance, and disease management measures. However, the burden attributable to inherited mutations is not well characterized. METHODS: We sequenced 1010 unrelated patients and families from across India with an indication of breast and/or ovarian cancers, using the TruSight Cancer panel which includes 14 genes, strongly associated with risk of hereditary breast and/or ovarian cancers...
February 22, 2018: Breast Cancer Research and Treatment
Dong Hoon Suh, Miseon Kim, Kyung Hun Lee, Keun Yong Eom, Maj Kamille Kjeldsen, Mansoor Raza Mirza, Jae Weon Kim
In 2017, 10 topics were selected as major clinical research advances in gynecologic oncology. For cervical cancer, efficacy and safety analysis results of a 9-valent human papillomavirus (HPV) vaccine and long-term impact of reduced dose of quadrivalent vaccine were updated. Brief introduction of KEYNOTE trials of pembrolizumab, a monoclonal antibody that blocks the interaction between programmed death (PD)-1 and its ligands, PD-L1 and PD-L2, followed. Tailored surveillance programs for gynecologic cancer related with Lynch syndrome and update on sentinel lymph node mapping were reviewed for uterine corpus cancer...
March 2018: Journal of Gynecologic Oncology
Christine Mau, Michael Untch
Risk-reducing surgery has proved to be a reasonable procedure in healthy women with a definitely elevated risk of developing cancer. Here we consider the elevated risk of breast and ovarian cancer. There is a clear indication for such surgery in healthy women with a pathogenic BRCA1/2 mutation. For these patients, a risk-reducing bilateral mastectomy leads to a verifiable reduction in mortality from breast cancer, particularly for young patients. In most cases, surgery is combined with breast reconstruction...
December 2017: Breast Care
Kevin H Eng, J Brian Szender, John Lewis Etter, Jasmine Kaur, Samantha Poblete, Ruea-Yea Huang, Qianqian Zhu, Katherine A Grzesik, Sebastiano Battaglia, Rikki Cannioto, John J Krolewski, Emese Zsiros, Peter J Frederick, Shashikant B Lele, Kirsten B Moysich, Kunle O Odunsi
Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute observing 892 informative pairs with 157 affected granddaughters. We performed germline X-chromosome exome sequencing on 186 women with ovarian cancer from the registry...
February 2018: PLoS Genetics
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