BRCA1 Mutation Carriers Research Articles

Risk-Reducing Breast and Gynecological Surgery for BRCA Mutation Carriers: A Narrative Review.

This narrative review aims to clarify the role of breast and gynecological risk-reduction surgery in BRCA mutation carriers. We examine the indications, contraindications, complications, technical aspects, timing, economic impact, ethical issues, and prognostic benefits of the most common prophylactic surgical options from the perspectives of a breast surgeon and a gynecologist. A comprehensive literature review was conducted using the PubMed/Medline, Scopus, and EMBASE databases. The databases were explored from their inceptions to August 2022. Three independent reviewers screened the items and selected those most relevant to this review's scope. BRCA1/2 mutation carriers are significantly more likely to develop breast, ovarian, and serous endometrial cancer. Because of the Angelina effect, there has been a significant increase in bilateral risk-reducing mastectomy (BRRM) since 2013. BRRM and risk-reducing salpingo-oophorectomy (RRSO) significantly reduce the risk of developing breast and ovarian cancer. RRSO has significant side effects, including an impact on fertility and early menopause (i.e., vasomotor symptoms, cardiovascular disease, osteoporosis, cognitive impairment, and sexual dysfunction). Hormonal therapy can help with these symptoms. Because of the lower risk of developing breast cancer in the residual mammary gland tissue after BRRM, estrogen-only treatments have an advantage over an estrogen/progesterone combined treatment. Risk-reducing hysterectomy allows for estrogen-only treatments and lowers the risk of endometrial cancer. Although prophylactic surgery reduces the cancer risk, it has disadvantages associated with early menopause. A multidisciplinary team must carefully inform the woman who chooses this path of the broad spectrum of implications, from cancer risk reduction to hormonal therapies.

Evaluation of inherited germline mutations in cancer susceptibility genes among pancreatic cancer patients: a single-center study

BackgroundGermline mutations in cancer susceptibility genes were identified in pancreatic cancer (PanC) patients with a sporadic disease and in those unselected for family cancer history.MethodsWith the aim to determine the prevalence of germline predisposition genes mutations in PanC, and to evaluate whether they were associated with the presence of PanC, we profiled a custom AmpliSeq panel of 27 cancer susceptibility genes in 47 PanC patients and 51 control subjects by using the Ion Torrent PGM system.ResultsMultigene panel testing identified a total of 31 variants in 27 PanC (57.4%), including variants with pathogenic/likely pathogenic effect, those of uncertain significance, and variants whose clinical significance remains currently undefined. Five patients carried more than one variant in the same gene or in different genes. Eight patients (17.0%) had at least one pathogenic/likely pathogenic variant in four main genes: CFTR (10.6%), BRCA2 (8.5%), ATM and CHEK2 (2.1%). Pathogenic/likely pathogenic mutation were identified in patients with positive PanC family history (20%) or in patients without first-degree relatives affected by PanC (13.6%). All the BRCA2 mutation carriers were unselected PanC patients. The presence of mutations in BRCA2 was significantly associated with an increased occurrence of PanC and with positive family history for endometrial cancer (p = 0.018).ConclusionsThis study confirmed the potential remarkable contribution of BRCA2 in assessing the presence of PanC. Overall our findings supported the recommendation of offering the germline testing to all the PanC patients with the intent to reduce the number of underdiagnosed carriers of mutations in predisposition genes, and not to preclude their relatives from the opportunity to benefit from surveillance programs.

BRCA, infertility, and fertility preservation: a review for counseling.

BRCA mutations as a triggering factor in breast cancer have been reported to result in fertility problems and oocyte aging in young patients with cancer diagnosis. These patients are concerned about fertility problems and family planning before undergoing treatment modalities that may result in infertility. In this review, we conducted analysis of the literature on the association between BRCA mutations and infertility, possible fertility preservation options, and their safety and tried to gather results from different disciplines and points of view on the matter. Our aim is to provide a general summary of recent studies to provide further insight on the matter for counseling BRCA mutation carriers on fertility preservation methods and their implications.

Financial toxicity in BRCA1 and BRCA2 carriers

ObjectiveFinancial toxicity (FT), the cumulative financial burden experienced due to medical care, is a well-established adverse effect of healthcare. Patients with BRCA mutations have significantly increased cancer risks compared to non-affected individuals, requiring more frequent screenings and, at times, prophylactic surgery, increasing their risk for FT. Our primary aim in this study was to describe rates of FT among BRCA carriers. MethodsWe performed a novel, cross-sectional study of FT in BRCA1/2 carriers. Participants were recruited via phone and/or email to complete consents and surveys on REDCap. The FACIT-COST tool, a validated tool for measuring FT, was used to assess FT; scores were divided into tertiles, with high FT defined as COST score < 24. Results265 BRCA positive female participants met enrollment criteria; 76 (28.7%) consented to participate and completed the survey. Participants were primarily non-Hispanic White (97.4%), privately insured (82.9%), and employed full time (67.1%). A significant proportion (22.7%) of participants reported delaying or avoiding care secondary to finances. No statistically significant association was seen between financial toxicity groups and analyzed demographics. Participants with high FT were more likely to engage in all surveyed cost-saving measures, with 41.7% of participants reporting delays/avoidance of care due to cost (p = 0.02). ConclusionsThis study of FT in BRCA carriers shows that financial toxicity exists as an issue in this high-risk patient population. This work serves as the first description of FT in BRCA mutation carriers and highlights the importance of incorporating routine counseling on cost when discussing recommendations for screening and clinical care with this patient population.

Long-Term Non-Cancer Risks in People with BRCA Mutations following Risk-Reducing Bilateral Salpingo-Oophorectomy and the Role of Hormone Replacement Therapy: A Review.

Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is the gold standard preventative option for BRCA mutation carriers at high risk for ovarian and breast cancer. However, when performed at the recommended ages of 35-45 years, RRBSO induces immediate premature surgical menopause, along with the accompanying adverse psychosocial, cardiovascular, bone, and cognitive health consequences. While these health consequences have been thoroughly studied in the general population, little is known about the long-term health outcomes in the BRCA population. Hormone replacement therapy (HRT) until the average age of natural menopause can help mitigate these health risks, yet the initiation of HRT is a complex decision among BRCA carriers due to concern of increasing the already high risk of breast cancer in these people. This review summarizes the current research on long-term non-cancer risks in BRCA carriers following RRBSO-induced premature surgical menopause, and highlights the existing evidence in support of HRT use in this population.

Survival Outcomes in Women with Unilateral, Triple-Negative, Breast Cancer Correlated with Contralateral Prophylactic Mastectomy.

Despite increased utilization of contralateral prophylactic mastectomy (CPM), there is insufficient evidence that it improves survival in average-risk women with unilateral breast cancer. CPM may be of heightened interest to patients with triple negative breast cancer (TNBC) because these patients are more likely to have BRCA1 mutation-associated disease and are not candidates for the chemoprevention benefits of adjuvant endocrine therapy. Survival and recurrence outcomes were evaluated for all TNBC patients from a multi-institutional database (1999-2018) at two academic cancer programs in two metropolitan cities of the Northeast and Midwest. Median follow-up time was 3.7years. Seven hundred and nighty six TNBC patients were evaluated and 15.45% underwent CPM. Women undergoing CPM were more likely to be white (p < 0.001), younger (p < 0.001), and underwent genetic testing (p < 0.001). A borderline survival benefit was observed for TNBC patients undergoing CPM (5-year overall survival 95.1% vs. 85.0%; p = 0.05). There was no difference in survival when BRCA mutation carriers were excluded (5-year overall survival 94.1% vs. 85.2%; p = 0.12). For BRCA mutation carriers, a numeric trend was observed for improved survival for patients undergoing CPM (5-year overall survival 97.2% vs. 84.1%; p = 0.35). Among patients not undergoing CPM, the rate of developing a new primary breast cancer was 2.2% (15/673). Among these 15 patients, 20% (3/15) were known BRCA mutation carriers. Our data demonstrate no survival benefit for TNBC patients without BRCA1/2 mutations undergoing CPM.

Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients.

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p < 0.0001). Twelve pre-/post-NACT tissue pairs obtained from BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication.

Hormone replacement therapy in BRCA mutation carriers: how shall we do no harm?

Women with a BRCA mutation have an increased risk of developing breast and ovarian cancer. Bilateral salpingo-oophorectomy is the only effective strategy to reduce this risk. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is recommended between the ages of 35 and 40 for women carriers of BRCA1 and between the ages of 40 and 45 for women carriers of BRCA1 and BRCA2 mutations. Most women undergo this procedure prior to their natural menopause subsequently developing an anticipated lack of hormones. This condition affects the quality of life and longevity, while it is more pronounced in women carrying a BRCA1 mutation compared to BRCA2 because they are likely to have surgery earlier. Hormone replacement therapy (HRT) is the only strategy able to significantly compensate for the loss of ovarian hormone production and counteract menopausal symptoms. There is strong evidence that short-term HRT use does not increase the risk of breast cancer among women with a BRCA1 mutation. Few data are available on BRCA2 mutation carriers. Therefore, BRCA mutation carriers require careful counseling about the outcomes of their RRSO, including menopausal symptoms and/or the fear associated with HRT use.

Prostate cancer risk, screening and management in patients with germline BRCA1/2 mutations.

Mutations in the BRCA1 and BRCA2 tumour suppressor genesare associated with prostate cancer risk; however, optimal screening protocols for individuals with these mutations have been a subject of debate. Several prospective studies of prostate cancer incidence and screening among BRCA1/2 mutation carriers have indicated at least a twofold to fourfold increase in prostate cancer risk among carriers of BRCA2 mutations compared with the general population. Moreover, BRCA2 mutations are associated with more aggressive, high-grade disease characteristics at diagnosis, more aggressive clinical behaviour and greater prostate cancer-specific mortality. The risk for BRCA1 mutations seems to be attenuated compared with BRCA2. Prostate-specific antigen (PSA) measurement or prostate magnetic resonance imaging (MRI) alone is an imperfect indicator of clinically significant prostate cancer; therefore, BRCA1/2 mutation carriers might benefit from refined risk stratification strategies. However, the long-term impact of prostate cancer screening is unknown, and the optimal management of BRCA1/2 carriers with prostate cancer has not been defined. Whether timely localized therapy can improve overall survival in the screened population is uncertain. Long-term results of prospective studies are awaited to confirm the optimal screening strategies and benefits of prostate cancer screening among BRCA1/2 mutation carriers, and whether these approaches ultimately have a positive impact on survival and quality of life in these patients.

The Role of Hormonal Replacement Therapy in BRCA Mutated Patients: Lights and Shadows.

All cancers develop as a result of mutations in genes. DNA damage induces genomic instability and subsequently increases susceptibility to tumorigenesis. Women who carry mutations of BRCA 1 and BRCA2 genes have an augmented risk of breast and ovarian cancer and a markedly augmented probability of dying because of cancer compared to the general population. As a result, international guidelines recommend that all BRCA1\2 mutation carriers be offered risk-reducing bilateral salpingo-oophorectomy at an early age to reduce the risk of cancer and decrease the mortality rate of this high-risk population. NCCN guidelines recommend risk-reducing bilateral salpingo-oophorectomy in pre-menopausal women, between 35-40 years in BRCA1 mutation carriers and between 40-45 years in BRCA2 mutation carriers. Unfortunately, the well-documented reduction of cancer risk is counterbalanced by early sterility and premature ovarian failure with an early onset of secondary menopausal syndromes such as neuromotor, cardiovascular, cognitive and urogenital deficiency. Hormonal replacement therapy significantly compensates for hormonal deprivation and counteracts menopausal syndrome morbidity and mortality; however, some data suggest a possible correlation between hormonal medications and cancer risk, especially in BRCA1\2 carriers who undergo long-term regimens. Conversely, short-term treatment before the age of natural menopause does not appear to increase the cancer risk in BRCA1 mutation carriers without a personal history of breast cancer after prophylactic surgery. Few data are available on BRCA2 mutation carriers and more well-designed studies are needed. In conclusion, clinicians should propose short-term hormone replacement therapy to BRCA 1 carriers to counteract hormonal deprivation; personalized counselling should be offered to BRCA2 mutation carriers for a balance between the risks and benefits of the treatment.

Radiation-Induced Lymphopoenia and Treatment Outcome in Hereditary Breast Cancer Patients.

Many breast cancer (BC) predisposition genes encode proteins involved in DNA damage repair (DDR). Identification of germline pathogenic va-riants (PV) in DDR genes raises the question whether their presence can influence the treatment outcomes and potential radiation-induced toxicity in their carriers treated by adjuvant radiotherapy, which has not yet been answered conclusively. We retrospectively examined records of 213 BC patients treated by adjuvant radiotherapy, including 39 (18.3 %) BRCA1/2 PV carriers, 25 carriers (11.7 %) of PV in other breast cancer-predisposing genes, and 149 (70 %) non-carriers. Our goal was to examine 5-year disease-free survival (5y DFS) rates among the study groups and determine the impact of radiotherapy-induced lymphopoenia (RIL) on this outcome. While we found no significant difference in 5y DFS between non-carriers and carriers of BRCA mutations (86.4 % vs 78.4 % P = 0.24) or between non-carriers and other studied mutations (86.4 % vs 93.3 %; P = 0.27), respectively, we observed that the entire group of PV carriers had a significantly lower proportion of patients without RIL (P = 0.04) than the non-carriers. In contrast, subsequent analyses indicated a non-significant trend toward an increased 5y DFS in PV carriers with RIL. Our single-centre study indicated that the presence of PV in BC patients has an insignificant impact on DFS but can reduce the risk of RIL associated with adjuvant radiotherapy. It remains unclear whether this may result from the paradoxical activation of anti-tumour immunity in PV carriers with higher lymphocyte consumption resulting from higher immune effectiveness.

Abstract IA024: Single nuclei chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry

Abstract Single nuclei analysis is allowing robust classification of cell types in an organ that helps to establish relationships between cell-type specific gene expression and chromatin accessibility status of gene regulatory regions. Using the institutional resource of breast tissues of healthy donors of various genetic ancestry, we have developed a comprehensive chromatin accessibility (snATAC-seq) and gene expression (snRNA-seq) atlas of human breast tissues. Our analyses included 51,367 nuclei with average sequence coverage of 1195 genes per nuclei. These nuclei were derived from 22 donors of Ashkenazi descent, 20 of European non-Ashkenazi ancestry, 10 of Asian ancestry, 10 Hispanic/Latina, 10 Native American, 6 from BRCA1 mutation carriers, and 5 from BRCA2 mutation carriers. Although tissues from 20 women of African Ancestry were included in sequencing, poor quality sequencing reads prevented inclusion of data from those samples in the final analysis. Integrated analysis revealed 10 distinct cell types in the healthy breast, which included three major epithelial cell subtypes (mature luminal, luminal progenitor, basal), two endothelial subtypes, two adipocyte subtypes, fibroblasts, T-cells, and macrophages. Mature luminal cells could be further divided into two distinct hormone sensitive subtypes, HSa and HSb, with HSa subtype expressing higher levels of Estrogen Receptor alpha (ESR1) and NEK10, a tyrosine kinase that controls p53 activity and limits cell proliferation. The luminal progenitors could be broadly classified into alveolar progenitors (AP) and basal-luminal hybrid progenitors (BL). AP cells expressed higher levels of ELF5, a known marker of alveolar cells, compared to BL cells. Basal cells could be classified into two subtypes with Basal-BAa cells being the most dominant and expressing higher levels of TP63 and NFIB compared to Basal-BAb cells. ESR1 expression pattern was distinctly different in tissues from Native Americans compared to the rest, with a high level of ESR1 expression extending to AP cells. In fact, overall AP cell numbers were ~3-fold higher in Native Americans compared to others (18.9% versus 1.5-8.8%). Furthermore, Ingenuity pathway analysis of differentially expressed genes revealed elevated Estrogen Receptor signaling in ML and AP cell types of Native Americans compared to those of other genetic ancestry. Despite significant differences in expression and activity in Native Americans compared to others, the chromatin accessibility map of the ESR1 gene regulatory regions in ML and LP cells did not show any genetic ancestry dependent variability. In general, cell subtype-specific gene expression did not correlate with chromatin accessibility differences, suggesting that transcriptional regulation independent of chromatin accessibility governs cell type-specific gene expression in the breast. Collectively, these results reveal complexities in gene expression in different cell types of the breast Citation Format: Poornima Bhat-Nakshatri, Duojiao Chen, Aditi Khatpe, Hongyu Gao, Yunlong Liu, Anna Maria Storniolo, Harikrishna Nakshatri. Single nuclei chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA024.

High grade acinic cell carcinoma of the breast with clear cytoplasm mimics clear cell carcinoma in a BRCA1 mutation carrier: a case report and review of the literature on the molecular analysis.

Acinic cell carcinoma of the breast is an extremely rare tumor. To the best of our knowledge, only one case is reported to have bilateral tumors and had both BRCA1 and TP53 mutation. Herein, we report another case of acinic cell carcinoma of the breast in a 29-years-old female carrying germline BRCA1 and TP53 mutation, and the tumor showed a complex combination of histological features which had not only the reported common features such as diffuse infiltrative small acinar or glandular structures mixed with solid nests, but also the uncommon widespread clear cells, high grade tumor cells. The immunohistochemical profile of the tumor cells was strongly positive for lysozyme and triple negative for ER, PR, HER2. Although she had bilateral high grade breast cancers, this patient refused postoperative adjuvant therapy this time and has been doing well in the past 12 months. As a rare form of triple-negative breast cancer with a relatively not so bad prognosis, more reports are needed to understand its biological characteristics.

Cancer mamar apărut în timpul tratamentului cu inhibitori PARP pentru un cancer ovarian cu mutaţie BRCA somatică – prezentare de caz

Breast and ovarian cancer are relatively frequent malig­nan­cies in BRCA mutation carrier patients. The synchronous pre­sence of these two cancers is a challenging clinical situation, es­pe­cial­ly in young women. We present a case report of a young woman diagnosed with high-grade serous ovarian car­ci­no­ma, somatic BRCA-mutant, who developed breast cancer during PARP inhibitor treatment. The right treatment choice for both malignancies may be equally thought-provoking for patient and doctor in face of recurrence risk reduction end­point. This case report emphasizes real life progression-free survival on PARP inhibitor treatment higher than in phase III clinical trials.

Pathologic Findings at Risk Reducing Surgery in BRCA and Non-BRCA Mutation Carriers: A Single-Center Experience.

Risk-reducing surgery (RRS) is recommended in BRCA-mutated carriers because of their increased risk of developing ovarian cancer, while its role is still discussed for women harboring mutations in non-BRCA homologous repair genes. The aim of this study was to retrospectively evaluate the occurrence of pathological findings in a high-risk population undergoing RRS in San Matteo Hospital, Pavia between 2012 and 2022, and correlate their genetic and clinical outcomes, comparing them with a control group. The final cohort of 190 patients included 85 BRCA1, 63 BRCA2, 11 CHEK2, 7 PALB2, 4 ATM, 1 ERCC5, 1 RAD51C, 1 CDH1, 1 MEN1, 1 MLH1 gene mutation carriers and 15 patients with no known mutation but with strong familial risk. Occult invasive serous carcinoma (HGSC) and serous tubal intraepithelial carcinoma (STIC) were diagnosed in 12 (6.3%) women, all of them BRCA carriers. No neoplastic lesion was diagnosed in the non-BRCA group, in women with familial risk, or in the control group. Oral contraceptive use and age ≤45 at surgery were both found to be favorable factors. While p53 signature and serous tubal intraepithelial lesion (STIL) were also seen in the control group and in non-BRCA carriers, STIC and HGSC were only found in BRCA1/2 mutation carriers.

Immune cells are increased in normal breast tissues of BRCA1/2 mutation carriers.

Breast cancer risk is elevated in pathogenic germline BRCA 1/2 mutation carriers due to compromised DNA quality control. We hypothesized that if immunosurveillance promotes tumor suppression, then normal/benign breast lobules from BRCA carriers may demonstrate higher immune cell densities. We assessed immune cell composition in normal/benign breast lobules from age-matched women with progressively increased breast cancer risk, including (1) low risk: 19 women who donated normal breast tissue to the Komen Tissue Bank (KTB) at Indiana University Simon Cancer Center, (2) intermediate risk: 15 women with biopsy-identified benign breast disease (BBD), and (3) high risk: 19 prophylactic mastectomies from women with germline mutations in BRCA1/2 genes. We performed immunohistochemical stains and analysis to quantitate immune cell densities from digital images in up to 10 representative lobules per sample. Median cell counts per mm2 were compared between groups using Wilcoxon rank-sum tests. Normal/benign breast lobules from BRCA carriers had significantly higher densities of immune cells/mm2 compared to KTB normal donors (all p < 0.001): CD8 + 354.4 vs 150.9; CD4 + 116.3 vs 17.7; CD68 + 237.5 vs 57.8; and CD11c + (3.5% vs 0.4% pixels positive). BBD tissues differed from BRCA carriers only in CD8 + cells but had higher densities of CD4 + , CD11c + , and CD68 + immune cells compared to KTB donors. These preliminary analyses show that normal/benign breast lobules of BRCA mutation carriers contain increased immune cells compared with normal donor breast tissues, and BBD tissues appear overall more similar to BRCA carriers.

BRCA mutation carriers suffering from ovarian cancer as a model for treatment decision in higher lines - Place for platinum reinduction.

Ovarian carcinoma is a malignancy with the highest mortality among gynecological cancers. Mutations in BRCA1/2 genes are believed to be a favorable prognostic factor and that, in general, the biological behavior of ovarian cancer in BRCA-positive individuals differs from others. However, some clinically relevant issues (i.e., prediction of response to chemotherapy and treatment of platinum-resistant BRCA-positive patients) remain unclear. (1) The aim of this study was to examine the prevalence of germline BRCA mutations in unselected recurrent ovarian cancer patient population, (2) analyze whether biological behavior of BRCA-positive tumors differs from others, and (3) analyze the effect of platinum reinduction in platinum-resistant BRCA-positive patients. This was a single-institution retrospective analysis. Consecutive recurrent ovarian cancer patients from years 2012 to 2020 were included; their BRCA1/2 mutational status was analyzed and correlated with progression-free survival (PFS), type of treatment, and response to treatment. Statistical significance of differences between and among patients was tested for continuous variables by the Mann-Whitney U-test or the Kruskal-Wallis test; a maximum likelihood Chi-square test was used for categorical variables. Two hundred and forty-three recurrent ovarian cancer patients were included. The median follow-up was 37 months. Pathogenic mutation in BRCA1 or BRCA2 gene was found in 18.1% of patients. There was no difference in PFS comparing BRCA-positive to BRCA-negative patients (median PFS: 10.2 vs. 10.1 months, P = 0.874); there was a difference in PFS comparing BRCA-negative versus BRCA-positive platinum-sensitive patients (9.4 vs. 14.3 months, P = 0.002). BRCA-positive platinum-resistant patients reinduced with platinum achieved a median PFS of 8 months (compared to those receiving nonplatinum treatment, median PFS: 4 months, P = 0.062). Germline BRCA mutations are not exclusive to platinum-sensitive ovarian cancer patients; even in platinum-resistant patients, mutation can be detected. We found no difference in PFS for platinum-sensitive BRCA-positive and BRCA-negative patients. Platinum reinduction may be considered for BRCA-positive platinum-resistant ovarian cancer patients to prolong PFS. Even these data describe only a small population, it supports the clinical practice of platinum-based chemotherapy use in platinum-resistant BRCA-positive patients.

In vivo assignment of methylmalonic acid in breast tissue using 2D MRS and relationship with breast density, menopausal status and cancer risk.

Methylmalonic acid (MMA) is linked to progression and aggressiveness of tumours. A recent study showed that high levels of circulatory MMA directed genetic programs promoting cancer progression. To evaluate in vivo two-dimensional correlated spectroscopy (2D COSY) data from women at elevated risk of breast cancer to determine if resonances consistent with MMA are present, and if so to correlate levels with breast density, menopausal status and risk categories. With institutional review board approval, 106 women at elevated risk (mean age 47), including 46 participants at medium risk, 43 at high risk with no known mutation and 17 BRCA-mutation carriers, were recruited. Breast density was assessed using a T2 sequence. A T1 sequence was used to place the voxel for the 2D COSY data. Peak volumes were normalized to the methylene peak at (1.30, 1.30)ppm. Chi-squared and Mann-Whitney tests were used. Two resonances are assigned on the diagonal at 3.15 ppm and 3.19 ppm consistent with and denoted MMA1 and MMA2 respectively. MMA1 and MMA2 increased in parallel with increased risk. BRCA-mutation carriers recorded an increase in mean MMA1 of 120% (p = 0.033) and MMA2 of 127% (p = 0.020) in comparison with participants with no known mutation. BRCA-mutation carriers with dense breasts recorded a significant increase in mean MMA1 of 137% (p = 0.002) and in mean MMA2 of 143% (p = 0.004) compared with BRCA-mutation participants with low-density breast tissue. MMA1 and MMA2 were higher in premenopausal women with dense breasts compared with those with low-density tissue. The highest values of MMA were recorded in BRCA-mutation carriers. Two tentative assignments are made for MMA in breast tissue of women at elevated risk for cancer. BRCA-mutation carriers exhibited higher values of MMA than those with no known mutation. Premenopausal women with BRCA mutation and dense breasts recorded the highest levels of MMA compared with other categories.

Proteomic signature for detection of high-grade ovarian cancer in germline BRCA mutation carriers.

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.

P070: Design of the INSIGHT study, evaluation of long-term follow-up care for lymphoma survivors in the Netherlands: does survivorship care at the BETER clinics reduce morbidity and mortality from late effects of lymphoma treatment and associated costs?

Background: Hodgkin lymphoma (HL) survivors are at substantial risks of serious late adverse treatment effects. The BETER consortium developed a nationwide infrastructure of outpatient clinics where 5-year HL survivors are screened and treated for adverse effects of lymphoma treatment according to nationally approved screening guidelines. BETER survivorship care includes risk-based screening for and treatment of (risk factors for) cardiovascular disease (CVD), breast cancer, hypothyroidism and (functional) asplenia. So far, evidence for the actual cost-effectiveness of structured cancer survivorship care in clinical practice is lacking. Current knowledge is based on simulation and modelling approaches and evidence from other populations (e.g. BRCA mutation carriers). In the INSIGHT study we will assess the (cost-)effectiveness of BETER survivorship care using data from clinical practice. Methods: The first BETER clinics started in 2013–2016 and the number of centres participating in BETER is quickly expanding: several centres started/will start a BETER clinic in 2021–2024. This allows for a retrospective cohort study with a quasi-experimental design to evaluate the effectiveness of BETER survivorship care by comparing survivors who did and did not receive BETER survivorship care. Once full nationwide implementation is in place, this comparison is no longer possible. In the INSIGHT study we will compare 450 HL survivors invited for BETER survivorship care in 2013–2016 with 450 matched survivors invited by a BETER clinic starting in 2021–2024, allowing for a median follow-up of ~8 years. The primary outcomes are burden of disease (in disability-adjusted life-years, DALYs) from CVD, breast cancer, hypothyroidism and (functional) asplenia, associated health care costs, quality of life and health-related productivity losses. Secondary outcomes are BETER clinic attendance, guideline adherence and knowledge and risk perception of late effects. In a cost-effectiveness analysis we will calculate costs/DALY and costs/QALY of BETER survivorship care. Conclusion: BETER is an internationally unique initiative of an elaborate infrastructure for adult oncology survivorship care. To our knowledge, INSIGHT is the first evaluation of (cost-)effectiveness of cancer survivorship care in clinical practice. The results will contribute to more effective, evidence-based long-term cancer survivorship care. At ISHL12 we will present design details as well as participation rates.