Germline Mutations In BRCA1 Research Articles

Metaplastic carcinoma of the breast and BRCA1 germline mutation: a case report and review

BackgroundMetaplastic carcinoma of the breast consists of both invasive ductal carcinoma and metaplastic carcinoma. This rare subtype of cancer has a poor prognosis. The development of metaplastic breast cancer and relationship with BRCA1 are not well known. Here, we report a rare case of germline BRCA1 mutation-positive breast cancer with chondroid metaplasia.Case presentationA 39-year-old Japanese woman with a family history of breast cancer in her mother and ovarian cancer in her maternal grandmother consulted at our hospital with a left breast mass. Needle biopsy for the mass was performed, leading to a diagnosis of invasive breast cancer with chondroid metaplasia. We performed left mastectomy + sentinel lymph node biopsy + tissue expander insertion and replaced with a silicone implant later. Pathological examination revealed that the patient had triple-negative breast cancer. Four courses of doxorubicin+ cyclophosphamide therapy were performed as adjuvant therapy after surgery. We performed genetic counseling and genetic testing, and the results suggested the germline BRCA1 mutation 307 T> A (L63*). She has currently lived without a relapse for 2 years post-surgery.ConclusionsThere have been only 6 cases of metaplastic breast carcinoma with germline BRCA1 mutations including our case. Patients with BRCA1 mutations may develop basal-like subtypes or M type of triple-negative breast cancer besides metaplastic breast cancers.

BRCA testing and outcomes in women with breast cancer.

Germline BRCA mutations (BRCAm) strongly influence the risk of developing breast cancer. This study aimed to understand the role of BRCAm testing in affected individuals and to assess its impact on the outcome of BRCAm carriers compared to non-carriers (BRCAwt) with breast cancer. The research question is "Does standard of care testing for BRCAm improve survival outcomes of breast cancer patients?" In a single institution observational cohort study, demographic and clinical characteristics were compared between breast cancer patients with and without BRCAm. Frequency of BRCA testing was assessed. Survival outcomes were assessed by initial treatment setting stratified by BRCA status. Of 5712 identified women with breast cancer, 14.6% (n = 835) were tested for a BRCA mutation and had a documented result. The total number and proportion of women tested for a BRCAm increased between 2000 and 2014, resulting in an increased number of BRCAm carriers identified. However, the proportion of women who underwent testing and had a BRCAm decreased during the study period from 27.5% in 2000-2004 to 13.3% in 2010-2014. Disease-free survival was similar in the adjuvant and neoadjuvant treatment settings between BRCAm and BRCAwt patients. Progression-free survival on first line treatment and overall survival for patients with metastatic disease was also similar between BRCAm and BRCAwt patients. The proportion of women tested and the number of BRCAm identified increased during the study period despite a decreasing proportion of positive results among women tested.

Preclinical evaluation of radiation therapy of BRCA1-associated mammary tumors using a mouse model.

Although germline mutations in BRCA1 highly predispose women towards breast and ovarian cancer, few substantial improvements in preventing or treating such cancers have been made. Importantly, BRCA1 function is closely associated with DNA damage repair, which is required for genetic stability. Here, we examined the efficacy of radiotherapy, assessing the accumulation of genetic instabilities, in the treatment of BRCA1-associated breast cancer using a Brca1-mutant mouse model. Treatment of Brca1-mutant tumor-engrafted mice with X-rays reduced tumor progression by 27.9% compared with untreated controls. A correlation analysis of irradiation responses and biomarker profiles in tumors at baseline identified differences between responders and non-responders at the protein level (pERα, pCHK2, p53, and EpCAM) and at the SOX2 target expression level. We further demonstrated that combined treatment of Brca1-mutant mammary tumors with irradiation and AZD2281, which inhibits PARP, significantly reduced tumor progression and extended survival. Our findings enhance the understanding of DNA damage and biomarker responses in BRCA1-associated mammary tumors and provide preclinical evidence that radiotherapy with synthetic DNA damage is a potential strategy for the therapeutic management of BRCA1-associated breast cancer.

Deep Learning and Digital Pathology Power Precision Treatment of Triple-Negative Breast Cancer

Background: Molecular stratification and tailored target therapy bring clinical benefit for patients with triple-negative breast cancer (TNBC), but it is difficult to implement comprehensive molecular testing in clinical practice. Thus, we aim to devise an approach based on digital pathology and deep learning for the molecular and prognostic stratification of TNBC. Methods: We collected digital whole slide images (WSIs) (N=425) of our previously established TNBC cohort with multi-omics data. A deep learning-based workflow was developed and applied to these WSIs to train and validate neural network models to predict multi-omics molecular features, to identify molecular subtypes, and to improve prognostic evaluation. The models that showed high prediction accuracy were further validated on the TNBC cases from TCGA (N=143). Findings: A model was first developed for automatic tissue type classification, which enabled selection of certain tissue types on WSIs for the following prediction. Numerous molecular features can be inferred from WSIs including the somatic PIK3CA mutation, germline BRCA2 mutation and PD-L1 expression. All of the four molecular subtypes of TNBC can be accurately identified based on WSIs and distinctive morphological patterns were revealed for each subtype. The addition of image features to clinical prognostic factors significantly improved the accuracy of relapse risk assessment. The models for predicting PIK3CA mutation, PD-L1 expression, TNBC subtypes and relapse risk can be well generalized to the TCGA TNBC cases. The complete prediction workflow along with validated models was modularized and deployed on an online platform, which can realize real-time one-stop prediction for newly-uploaded WSIs. Interpretation: We proposed a deep learning-based workflow and developed neural network models to predict clinically relevant information of TNBC from pathological WSIs. Our findings and established platform may enable the implementation of artificial intelligence guided precision treatment in clinical trials and future routine practice. Funding: Fudan University Shanghai Cancer Center. Declaration of Interest: None to declare Ethical Approval: The tissue samples used in our study were obtained after the approval from the FUSCC Ethics Committee.

Novel Therapies for Metastatic Triple-Negative Breast Cancer: Spotlight on Immunotherapy and Antibody-Drug Conjugates.

Background: Triple-negative breast cancer (TNBC) is a biologically heterogeneous disease that is often associated with worse outcomes compared with other subtypes such as hormone receptor-positive tumors and HER2-positive tumors. While chemotherapy remains the mainstay of standard therapy for metastatic TNBC (mTNBC), several novel treatments have been developed over the past few years. In this review article, we review the major developments in the management of patients with mTNBC. Summary: The combination of chemotherapy and immunotherapy is a potential therapeutic option for PD-L1-positive mTNBC, as the FDA recently approved atezolizumab (Tecentriq) and pembrolizumab (Keytruda) in combination with chemotherapy. Also, 2 targeted therapies-olaparib (Lynparza) and talazoparib (Talzenna)-are FDA approved for the management of mTNBC with germline BRCA mutations, and sacituzumab govitecan, an anti-Trop2 antibody-drug conjugate (ADC), was recently approved for previously treated mTNBC. A number of promising therapies are on the horizon, including AKT inhibitors for PI3K-altered TNBC as well as other ADCs. Key Message: The successful clinical development of immunotherapies, PARP inhibitors, and ADCs for the management of mTNBC has improved the survival outcome of patients. Over the coming years, the therapeutic developments in precision medicine will likely change the mTNBC landscape, and might make the current definition of TNBC as breast cancer that is estrogen receptor negative, progesterone receptor negative, and HER2 negative obsolete.

PARP Inhibitors in Triple-Negative Breast Cancer Including Those With BRCA Mutations.

Poly(ADP-ribose) polymerase (PARP) is involved in single-strand DNA break base excision repair. PARP inhibition causes synthetic lethality in breast cancers associated with germline BRCA1 and BRCA2 mutations and is routinely used in clinical practice for metastatic breast cancer. Breast cancers with homologous recombination deficiency or BRCAness, most commonly triple-negative breast cancers, may also benefit. Currently, PARP inhibitor use for triple-negative breast cancer with wild-type BRCA does not have definitive efficacy; however, this is an area of active research. Further clinical and translational data may identify additional patient populations that will benefit from PARP inhibitor therapy.

Epidemiology of Triple-Negative Breast Cancer: A Review.

Triple-negative breast cancer accounted for 12% of breast cancers diagnosed in the United States from 2012 to 2016, with a 5-year survival 8% to 16% lower than hormone receptor-positive disease. However, preventive and screening strategies remain tailored to the demographics of less lethal luminal cancers. This review examines the ethnic, genetic, and modifiable risk factors associated with triple-negative breast cancer, which providers must recognize to address the societal disparities of this deadly disease. Most notable is that triple-negative cancers disproportionately affect African American women and carriers of germline BRCA and PALB2 mutations. Even controlling for treatment delays, stage, and socioeconomic factors, African Americans with triple-negative breast cancer remain nearly twice as likely to die of their disease. To level the playing field, we must integrate genomic predictors of disease and epidemiologic characteristics of molecular breast cancer subtypes to provide personalized risk assessment, screening, and treatment for each patient.

Germline and Somatic mutations in postmenopausal breast cancer patients

OBJECTIVES:In breast cancer (BC) patients, the frequency of germline BRCA mutations (gBRCA) may vary according to the ethnic background, age, and family history of cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the second most common somatic mutated gene in BC; however, the association of mutations in both genes with cancer has not been thoroughly investigated. Thus, our aims were to investigate gBRCA mutation frequency in a cohort of postmenopausal Brazilian BC patients and the association of gBRCA1/BRCA2 and PIK3CA somatic mutations.METHODS:Forty-nine postmenopausal (>55 years) and forty-one young (≤35 years) BC patients were included in this study. The postmenopausal group included patients who reported a positive family history of cancer. For these patients, gBRCA1/BRCA2 were sequenced using next-generation sequencing (NGS) or Sanger sequencing. Data for gBRCA in young patients were already available from a previous study. DNA from formalin-fixed, paraffin-embedded (FFPE) tumors was obtained from 27 postmenopausal and 41 young patients for analyzing exons 9 and 20 of PIK3CA. The association between gBRCA1/BRCA2 and somatic mutations in PIK3CA was investigated.RESULTS:The overall frequency of gBRCA1/BRCA2 among the 49 postmenopausal patients was 10.2%. The frequencies of somatic mutations in PIK3CA in the postmenopausal and young patients were 37% and 17%, respectively (ns). The most common PIK3CA mutation was found to be E454A. Nonsense and frameshift mutations, which may counteract the oncogenic potential of PIK3CA were also detected. Regardless of age, 25% of BRCA1/BRCA2 mutation carriers and non-carriers , each, had PIK3CA somatic mutations.CONCLUSIONS:Data obtained indicate that BRCA1/BRCA2 gene testing may be considered for postmenopausal patients with BC who have a family history of cancer. Although some of them are not considered pathogenic, somatic variants of PIK3CA are frequently observed in BC patients, especially in postmenopausal patients.

A survey on improving validation in plasma samples by niraparib and LC-MS/MS methods

The objective of an exit survey is to improve and authorize a rapid and efficient “liquid chromatography-tandem mass spectrometry (LC-MS/MS)” technique for examination of Niraparib in plasma samples. Niraparib was separated utilizing “X-Bridge C18, 50 x 4.6 mm”, 5 µm column with MP composed of 10 mM Methanol &Ammonium format in a proportion of (20:80 v/v). MRM positive mode is utilized to identify the Niraparib at 321.5®195.4. The approach illustrates sinter &intra- day precision surrounded by0.7 to 2.0 and 0.7 to 2.7 % and accuracy within 101.4-102.4 & 99.5-104.8 %. Germline mutations in BRCA1 and 2, two genes associated with mechanisms of DNA reparation impairment, are appeared to be connected with breast incidence and malignant ovarian growth, both irregular& familiar. PARP is a group of enzymes engaged with BER system. The presentation of PARP inhibitors in patients with BRCA-transformed ovarian malignant growth is associated with the synthetic lethality concept. Niraparib (NR) is an inhibitor of "poly (ADP-ribose) polymerase (PARP) enzymes", PARP-1, and PARP-2 performs a character in DNA restoration. We observed such vast numbers of challenges with the revealed strategies regarding stability &reproducibility for long-run analysis. It is crucial to building up the tremendous bioanalytical method with appropriate Deuterated or analog-based internal standard in terms of reproducibility and matrix effect.

BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor.

Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response.

Cost-Effectiveness Analysis of Maintenance Olaparib in Patients with Metastatic Pancreatic Cancer and a Germline BRCA1/2 Mutation Based on the POLO Trial.

ObjectiveThe phase III POLO trial demonstrated that olaparib as maintenance therapy for metastatic pancreatic cancer patients with a germline BRCA mutation had greater efficacy than placebo, but maintenance olaparib places an economic burden on patients. This study evaluated the cost-effectiveness of olaparib as maintenance therapy based on the POLO trial (NCT02184195).MethodsA three-state Markov model (progression-free survival [PFS], progressive disease [PD] and death) based on data from the POLO trial was used to estimate the incremental cost-effectiveness ratio (ICER) of maintenance olaparib versus placebo for metastatic pancreatic cancer patients with a germline BRCA mutation. The cost was evaluated from the Chinese society’s perspective, and health outcomes were assessed in terms of quality-adjusted life years (QALYs). The primary outcome was the ICER gained in terms of 2019 US$ per QALY. Model robustness was explored with one-way and probabilistic sensitivity analyses.ResultsCompared with placebo, maintenance olaparib increased costs by $23,544.35 while gaining 0.69 QALYs, resulting in an ICER of $34,122.25 per QALY. The ICER was far higher than the commonly accepted willingness-to-pay threshold ($28,255.55 per QALY).ConclusionCompared with placebo, maintenance olaparib for metastatic pancreatic cancer patients with a germline BRCA mutation is not cost-effective in China.

Factors associated with use of hormone therapy after preventive oophorectomy in BRCA mutation carriers

Bilateral salpingo-oophorectomy (oophorectomy) is recommended to women with a germline BRCA1 or BRCA2 mutation before natural menopause to prevent ovarian and fallopian tube cancer. The adverse effects of early surgical menopause are well established. Although many of the side effects can be ameliorated by the use of hormone therapy (HT); use of HT in this group of predominantly young patients remains suboptimal. The goal of this study was to identify the frequency of HT use, as well as predictors of HT uptake in BRCA mutation carriers who underwent preventive oophorectomy before natural menopause. Eligible participants were identified from a longitudinal study of BRCA mutation carriers. We included premenopausal women with no personal history of cancer who underwent oophorectomy before age 50 and who had a minimum of 2 years of follow-up. Detailed information on HT use and other important variables was collected by a research questionnaire every 2 years. Descriptive statistics were used to evaluate the use of HT in various subgroups. A total of 793 women with a BRCA1 or BRCA2 mutation were included in this analysis. The mean age at oophorectomy was 42 years (range 28-49). Sixty-one percent of the women reported using HT after oophorectomy. Factors associated with HT use included young age at surgery, a high level of education and preventive mastectomy. The uptake of HT after oophorectomy in women with a BRCA1 or BRCA2 mutation varies by age, education, and surgical history. Clinician and patient awareness may lead to better utilization of HT in women who undergo oophorectomy at an early age to help mitigate the adverse effects associated with surgical menopause.

BRCAness as a prognostic indicator in patients with early breast cancer

BRCAness is defined as a phenotypic copy of germline BRCA mutations, which describes presence of homologous recombination defects in sporadic cancers. We detected BRCAness by multiplex ligation-dependent probe amplification (MLPA) and explored whether BRCAness can be used as a predictor of prognosis. BRCAness status was classified for total 121 breast cancer patients. Forty-eight patients (39.7%) were identified as BRCAness positive. Tumors of BRCAness were more likely to be hormone receptors negative (95.8% vs. 50.7%, P < 0.001), nuclear grade III (76.1% vs. 48.4%, P = 0.001) and triple-negative breast cancer subtype (91.6% vs. 42.5%, P < 0.001). Five-year disease free survival (DFS) (54.0% vs. 88.0%, P < 0.001) and overall survival (OS) (76.3% vs. 93.1%, P = 0.002) were significantly lower in BRCAness patients. In neoadjuvant chemotherapy subgroup analysis, clinical response rate for taxane-based regimen was significantly lower in BRCAness patients (58.3% vs. 77.8%, P = 0.041). Cox regression multivariate analysis showed that BRCAness was the independent prognostic factor for DFS (HR 2.962, 95%CI 1.184–7.412, P = 0.020), but not for OS (HR 2.681, 95%CI 0.618–11.630, P = 0.188). BRCAness is associated with specific characteristics and may suggest resistance to taxane-based chemotherapy. BRCAness can be used as a negative prognostic indicator for breast cancer.

Tumor phenotype and concordance in synchronous bilateral breast cancer in young women.

Synchronous bilateral breast cancer is uncommon, and its pattern and incidence among younger women is unknown. Here we report the incidence, phenotypes, and long-term oncologic outcomes of bilateral breast cancer in women enrolled in the Young Women's Breast Cancer Study (YWS). The YWS is a multi-center, prospective cohort study of women with breast cancer diagnosed at age ≤ 40years. Those with synchronous bilateral breast cancer formed our study cohort. Tumor phenotypes were categorized as luminal A (hormone receptor (HR)+/HER2-/grade 1/2), luminal B (HR+ /HER2+ or HER2- and grade 3), HER2-enriched (HR-/HER2+), or basal-like (HR-/HER2-). Descriptive statistics were used to evaluate tumor phenotypes of bilateral cancers for concordance. Among 1302 patients enrolled in the YWS, 21 (1.6%) patients had synchronous bilateral disease. The median age of diagnosis was 38years (range 18-40years). Seventeen (81.0%) underwent genetic testing with 6 found to have pathogenic germline mutations in BRCA1, BRCA2, or TP53. The majority of patients (76.2%) underwent bilateral mastectomy. On pathology, 2 patients had bilateral in-situ disease, 6 had unilateral invasive and contralateral in-situ disease, and 13 had bilateral invasive disease. Of those with bilateral invasive disease, 10 (76.9%) had bilateral luminal tumors and, when fully characterized, 6 were of the same luminal subtype. Only 1 patient had bilateral basal-like breast cancer. At median follow-up of 8.2years, 14 patients are alive with no recurrent disease. Bilateral breast cancer is uncommon among young women diagnosed with breast cancer at age ≤ 40. In our cohort, the majority of invasive tumors were of the luminal phenotype, though some differed by grade or HER2 status. These findings support the need for thorough pathologic workup of bilateral disease when it is found in young women with breast cancer to determine risk and tailor treatment.

Abstract IA-09: The end of perpetual chemotherapy?

Abstract The traditional therapeutic model for patients with metastatic pancreatic cancer is perpetual chemotherapy from diagnosis to death. However, subsets of patients who achieve durable responses to cytotoxic chemotherapy may benefit from a switch maintenance approach. Maintenance therapy with the PARP inhibitor olaparib has recently been established for one such subgroup: Patients with germline BRCA mutations. In this talk we will review the available data and the future directions for maintenance therapy including combination treatments and expanding beyond germline BRCA carriers. Citation Format: Kim A Reiss. The end of perpetual chemotherapy? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-09.

Gastric Cancer in BRCA1 Germline Mutation Carriers: Results of Endoscopic Screening and Molecular Analysis of Tumor Tissues

Introduction: There is some evidence suggesting a link between BRCA1/2 germline mutations and increased risk of gastric cancer. Methods: Endoscopic screening for stomach malignancies was performed in 120 BRCA1 mutation carriers in order to evaluate the probability of detecting the tumor disease. Results: No instances of gastric cancer were revealed at the first visit. The analysis of atrophic changes performed by OLGA (Operative Link for Gastritis Assessment) criteria revealed that OLGA stages I–IV alterations were observed in 26 of 41 (63%) subjects aged >50 years as compared to 29 of 79 (37%) in younger subjects (p = 0.007, χ² test). One BRCA1 mutation carrier developed gastric cancer 4 years after the first visit for endoscopic examination. We performed next-generation sequencing analysis for this tumor and additional 4 archival gastric cancers obtained from BRCA1/2 mutation carriers. Somatic loss of the remaining BRCA1/2 allele was observed in 3 out of 5 tumors analyzed; all of these carcinomas, but none of the malignancies with the retained BRCA1/2 copy, showed chromosomal instability. Conclusion: Taken together, these data justify further studies on the relationships between the BRCA1/2 and gastric cancer.

Therapy Related Myeloid Neoplasm Post PARP Inhibitors: Potential Clonal Selection.

Introduction Clonal selection is one of the mechanisms leading to therapy-related myeloid neoplasms (TRMN). A preexisting somatic mutation in hematopoietic stem cell (defined as clonal hematopoiesis [CH]) emerges under pressure of chemotherapy or radiotherapy, leading to TRMN development. Most of these mutations belong to the DNA damage response (DDR) pathway as TP53 or PPM1D mutations and are known to confer a dismal prognosis. Recently authorized for the treatment of ovarian cancers (OC), the poly (ADP-ribose) polymerase inhibitors (PARPi) represent a promising targeted therapy. However, by inducing DNA damage and altering DNA repair process, PARP inhibition could represent a challenge for the genetic stability of the healthy tissues. Thus, we assessed the effect of PARP inhibition on the development of CH and TRMN after PARPi treatment for OC (TRMN-PARPi) in combination with chemotherapies. Methods Firstly, we performed a targeted 77 genes mutational analysis using Next Generation Sequencing (NGS) in 13 patients exposed to PARPi without TRMN. Secondly, we retrospectively identified, with the help of the UNIHEM group of Unicancer, 17 patients who experienced TRMN-PARPi. Clinical, biological and survival data were collected and compared to 23 OC patients with TRMN not treated with PARPi (Gustave Roussy institutional database). Lastly, NGS was performed for 3 patients with TRMN-PARPi with sequential sampling. Patient's samples were obtained with informed consent. Results Thirteen OC patients during maintenance treatment with PARPi without TRMN were explored by NGS. Median age at NGS was 64.5 years old (yo) (40.5-75.3). 4/13 (31%) patients harbored BRCA1/2 germline mutation. Time between OC diagnosis and NGS was 4.3 y (1-11.6). The median number of chemotherapy line at PARPi initiation was 2 (1-3). 7 received Olaparib, 5 Niraparib and 1 Rucaparib. The median duration of PARPi treatment before NGS was 4.7 months (1.1-25.1). 12/13 patients experienced hematological toxicities during the PARPi treatment. CH was found in 10/13 (77%) patients (Figure 1a), including mutations of DDR genes in 8/10 (80%). 6/8 (75%) patients had 2 or more gene mutations. Next we identified 17 cases of TRMN occurring during or after PARPi administration for OC (6/17 [35%] t-AML and 11/17 [65%] t-MDS). 12/17 (71%) patients had BRCA germline mutations (7 BRCA1 and 5 BRCA2). All received Olaparib with a median dose of 600mg/d (400-1200). Median duration of Olaparib treatment was 1.7 years (0.2-4.6). TRMN-PARPi were described 1.4 months (0-10.9) after the end of PARPi administration. We compared these patients to a cohort of TRMN post OC not treated by PARPi. Number of therapy lines for OC, time between TRMN and OC diagnosis, median age at TRMN, were, for TRMN-PARPi, 2 (1-8), 5.9 y (0.9-20.8), 64.4 yo (46-74); respectively, compared to 3 (1-8), 4.9 y (1.7-36.9), 59.3 yo (35.7-85.7); (p=ns). TRMN-PARPi cytogenetic was unfavorable for 16/17 (94%) (including 11/17 [65%] complex karyotype) compared to 16/23 (70%) (11/23 [48%] complex karyotype). C Median survival was significantly lower in the TRMN-PARPi group 3.9 months 95%CI [2.0-9.7] and 6.1 months 95%CI [4.1-15.8] respectively, p=0.046, Fig 1b). However, median survival from OC diagnosis was not different between the two groups 6.2 y 95%CI [5.6-NA] for TRMN-PARPi vs 5.6 y 95%CI [5.0-11.6]. NGS was available for 8/17 TRMN-PARPi and revealed mutations in DDR genes in 7/8 patients (6 patients with TP53 mutation, 2 with PPM1D mutation). For 3 patients, we had samples from OC stage, before PARPi administration. We found that mutations from TRMN stage were present at lower frequency, confirming clonal selection by PARPi treatment (Figure 1c). Conclusions Here we described, for the first time, a cohort of TRMN patients previously treated with PARPi for an OC. Intriguingly, most of these TRMN occurred with a short latency at the end of PARPi treatment, with unfavorable cytogenetic and very short OS. Moreover, we found a very high percentage of CH involved in the DDR pathway (62%) in patients under PARPi treatment without TRMN suggesting a potential clonal selection which could lead ultimately to TRMN. PARPi are now indicated in 1rst line high grade OC regardless of BRCA status, which should expand indications. Benefit for OC patients is not questionable; however, caution will be warranted for patients with CH before PARPi treatment, especially implicating DDR mutations. Disclosures Etienne: Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

Clinical Characteristics and Prognosis of Gastric Cancer Patients with BRCA 1/2 Germline Mutations: Report of Ten Cases and a Literature Review.

BackgroundThe prognosis of gastric cancer (GC) is poor with a median overall survival (OS) of less than 12 months in advanced-stage disease. The search for distinct genetic subgroups of GC patients and predictive biomarkers is ongoing. While BRCA1 or BRCA2 germline mutations (gBRCAm) have potential therapeutic implications in ovarian, breast and pancreatic cancers, their significance in GC patients has not been established.Patients and MethodsA retrospective multi-center data analysis of GC patients with gBRCAm was conducted, detailing the clinical characteristics and disease course in this unique subset of patients.ResultsTen GC patients with gBRCAm were identified, six of them with metastatic disease. The median OS of all ten GC patients was 47.5 (13–192) months. Median OS for patients diagnosed with operable disease was 55.5 (13–192) months and of the patients with metastatic disease (calculated from metastatic disease diagnosis) 32 (15–52) months with an exceptional 1-, 2- and 3-year survival rate of 100%, 83.3% and 50%, respectively.ConclusionThese preliminary data suggest that gBRCAm in GC patients are associated with a favorable prognosis. Furthermore, gBRCAm might be a predictive biomarker to DNA-damaging agents response in GC patients, similarly to its established role in other malignancies. Further research is needed to confirm our findings.

Cost-Effectiveness of Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer.

Maintenance therapy with the PARP inhibitor olaparib for metastatic pancreatic cancer (MPC) with a germline BRCA1 or BRCA2 mutation has been shown to be effective. We aimed to evaluate the cost-effectiveness of maintenance olaparib for MPC from the US payer perspective. A partitioned survival model was adopted to project the disease course of MPC. Efficacy and toxicity data were gathered from the Pancreas Cancer Olaparib Ongoing (POLO) trial. Transition probabilities were estimated from the reported survival probabilities in each POLO group. Cost and health preference data were derived from the literature. The incremental cost-utility ratio, incremental net-health benefit, and incremental monetary benefit were measured. Subgroup analysis, one-way analysis, and probabilistic sensitivity analysis were performed to explore the model uncertainties. Maintenance olaparib had an incremental cost-utility ratio of $191,596 per additional progression-free survival (PFS) quality-adjusted life-year (QALY) gained, with a high cost of $132,287 and 0.691 PFS QALY gained, compared with results for a placebo. Subgroup analysis indicated that maintenance olaparib achieved at least a 16.8% probability of cost-effectiveness at the threshold of $200,000/QALY. One-way sensitivity analyses revealed that the results were sensitive to the hazard ratio of PFS and the cost of olaparib. When overall survival was considered, maintenance olaparib had an incremental cost-utility ratio of $265,290 per additional QALY gained, with a high cost of $128,266 and 0.483 QALY gained, compared with results for a placebo. Maintenance olaparib is potentially cost-effective compared with placebo for patients with a germline BRCA mutation and MPC. Economic outcomes could be improved by tailoring treatment based on individual patient factors.

BRCA1 Mutations in Cancer: Coordinating Deficiencies in Homologous Recombination with Tumorigenesis.

Cancers that arise from BRCA1 germline mutations are deficient for homologous recombination (HR) DNA repair and are sensitive to DNA-damaging agents such as platinum and PARP inhibitors. In vertebrate organisms, knockout of critical HR genes including BRCA1 and BRCA2 is lethal because HR is required for genome replication. Thus, cancers must develop strategies to cope with loss of HR activity. Furthermore, as established tumors respond to chemotherapy selection pressure, additional genetic adaptations transition cancers to an HR-proficient state. In this review, we discuss biological mechanisms that influence the ability of BRCA1-mutant cancers to perform HR. Furthermore, we consider how the HR status fluctuates throughout the cancer life course, from tumor initiation to the development of therapy refractory disease.