Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous ...recombination DNA repair genes is uncertain.
Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway.
Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation.
Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials.
Inherited loss-of-function mutations in BRCA1 and BRCA2 and other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due to inherited mutations is not known. ...Using targeted capture and massively parallel genomic sequencing, we screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma. Subjects were consecutively enrolled at diagnosis and not selected for age or family history. All classes of mutations, including point mutations and large genomic deletions and insertions, were detected. Of 360 subjects, 24% carried germ-line loss-of-function mutations: 18% in BRCA1 or BRCA2 and 6% in BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53. Six of these genes were not previously implicated in inherited ovarian carcinoma. Primary carcinomas were generally characterized by genomic loss of normal alleles of the mutant genes. Of women with inherited mutations, >30% had no family history of breast or ovarian carcinoma, and >35% were 60 y or older at diagnosis. More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
•Physical activity improves quality of life in cancer survivors.•We discuss the role of physical activity in breast and gynecologic cancer survivors.•We provide guidelines for exercise prescription ...and a practical guide for clinicians.
Physical activity improves physical functioning, cancer-related symptoms, and quality of life in cancer survivors, and is beneficial across all phases of survivorship. Observational studies suggest that high levels of physical activity may also improve cancer outcomes such as survival, but randomized controlled trials of exercise interventions in oncology patients with survival outcomes as a primary endpoint are needed and ongoing. This review focuses on the role of physical activity in breast and gynecologic cancer survivorship, based on the available evidence. It discusses specific guidelines for exercise prescription, highlights the role of the clinician in promoting physical activity, and provides useful resources for cancer survivors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Women with germline BRCA1 or BRCA2 (BRCA) mutations, are recommended risk-reducing salpingo-oophorectomy (RRSO) prior to menopause. Surgical menopause has significant impact on patients' health and ...well–being. Subsequently, concerns about surgical menopause influence uptake of RRSO in high risk women. The role of hormone replacement therapy (HRT) in BRCA mutation carriers undergoing RRSO has been controversial. In the general population, premature surgical menopause is associated with worse quality of life and cognitive function, and increased risk of bone and cardiovascular disease; HRT continued until the natural age of menopause is shown to alleviate a number of these effects. Conflicting information has been published on HRT and breast cancer risk. For BRCA mutation carriers, potential augmentation of already elevated breast cancer risk is of great concern. In this article, we provide a review of the literature on HRT in this high-risk population, including effects on quality of life, cardiovascular, bone, and brain health. We also review impact of HRT on breast cancer risk, with a discussion of HRT formulation and surgical approach. Though evidence is limited, HRT after RRSO has a number of reported benefits and does not appear to impact breast cancer risk reduction in BRCA mutation carriers. This information is critical when discussing RRSO with patients, as providers should review risks of early menopause and treatment options. This review provides information to assist with counseling this specific population.
•Hormone replacement therapy use improves endocrine symptoms and sexual function after premature surgical menopause.•In BRCA mutation carriers, breast cancer risk is not altered by estrogen replacement therapy after oophorectomy.•Progestin containing hormonal regimens may have a less favorable breast cancer risk profile for BRCA mutation carriers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract In the past, hereditary ovarian carcinoma was attributed almost entirely to mutations in BRCA1 and BRCA2 , with a much smaller contribution from mutations in DNA mismatch repair genes. ...Recently, three new ovarian cancer susceptibility genes have been identified: RAD51C , RAD51D , and BRIP1 . In addition, germline mutations in women with ovarian carcinoma have been recently identified in many of the previously identified breast cancer genes in the Fanconi anemia (FA)–BRCA pathway. While mutations in genes other than BRCA1 and BRCA2 are each individually rare, together they make up a significant proportion of cases. With at least 16 genes implicated in hereditary ovarian cancer to date, comprehensive testing for ovarian cancer risk will require assessment of many genes. As the cost of genomic sequencing continues to fall, the practice of evaluating cancer susceptibility one gene at a time is rapidly becoming obsolete. New advances in genomic technologies will likely accelerate the discovery of additional cancer susceptibility genes and increase the feasibility of comprehensive evaluation of multiple genes simultaneously at low cost. Improved recognition of inherited risk will identify individuals who are candidates for targeted prevention. In addition, identifying inherited mutations in a variety of FA–BRCA pathway genes may aid in identifying individuals who will selectively benefit from PARP inhibitors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The presence of tumor infiltrating lymphocytes (TIL) and defects in homologous recombination (HR) are each important prognostic factors in ovarian carcinoma (OC). We characterized the association ...between HR deficiency (HRD) and the presence of TILs in a cohort of OC patients and the relative contribution to overall survival.
Patients with carcinoma of the ovary, fallopian tube, or peritoneum were prospectively enrolled. Malignant neoplasm and serum samples were collected. Immunohistochemistry for CD3+ T cells and CD68+ tumor associated macrophages (TAMs) was performed on specimens collected at primary surgery. Damaging germline and somatic mutations in genes in the HR-mediated repair (HRR) pathway were identified using BROCA sequencing. HRD was defined as a damaging mutation in one of 12 genes in the HRR pathway or promoter hypermethylation in BRCA1 or RAD51C.
Ninety-eight of 250 patients included in the analysis had HRD OC (39.2%). HRD OC were enriched for CD3+ TILs and CD68+ TAMs. High CD3+ TIL was present in 65.3% of HRD OC compared to 43.4% of non-HRD OC (P = 0.001). High CD68+ TAM was present in 66.3% of HRD OC compared to 50.7% of non-HRD OC (P = 0.015). Patients with HRD OC and high CD3+ TILs had the longest median overall survival compared to non-HRD OC with low CD3+ TILs (70.9 vs. 35.8 months, adjusted HR 0.38, 95% CI (0.25–0.59)).
Patients that have both CD3+ TILs and HRD OC are afforded the greatest improvement in overall survival. This finding may have therapeutic implications for OC patients treated with emerging immunotherapies.
•Homologous recombination deficient (HRD) ovarian carcinoma (OC) is enriched for CD3+ tumor infiltrating lymphocytes (TIL).•Patients with both CD3+ TILs and HRD OC have the greatest overall survival, which may have therapeutic implications.•These findings highlight differences in the tumor microenvironment that could contribute to differential responses.•This is especially relevant as novel immunotherapies are being tested for the treatment of ovarian carcinoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
In ovarian carcinoma, mutations in homologous recombination DNA repair (HRR) genes, including BRCA1 and RAD51C, are associated with increased survival and specific clinical features. Promoter ...hypermethylation is another mechanism of reducing gene expression. We assessed whether BRCA1 and RAD51C promoter hypermethylation is associated with similar survival and clinical characteristics.
Promoter methylation of BRCA1 and RAD51C was evaluated using methylation-sensitive PCR in 332 primary ovarian carcinomas. Damaging germline and somatic mutations in 16 HRR genes were identified using BROCA sequencing.
BRCA1 methylation was detected in 22 carcinomas (6.6%) and RAD51C methylation in 9 carcinomas (2.7%). These small numbers limited the power to detect differences in survival and platinum sensitivity. Mutations in one or more HRR genes were found in 95 carcinomas (29%). Methylation of BRCA1 or RAD51C was mutually exclusive with mutations in these genes (P=0.001). Patients whose carcinomas had BRCA1 methylation (57.7years±2.5) or BRCA1 mutations (54.1years±1.4) were younger than those without (63.3years±0.8; P=0.029, P<0.0001). BRCA1 methylation and germline BRCA1 mutation were associated with high grade serous (HGS) histology (P=0.045, P=0.001). BRCA1 mutations were associated with increased sensitivity to platinum chemotherapy while BRCA1 methylation was not (P=0.034, P=0.803). Unlike HRR mutations, methylation was not associated with improved overall survival compared to cases without methylation or mutation.
Patients with BRCA1-methylated carcinomas share clinical characteristics with patients with BRCA1-mutated carcinomas including younger age and predominantly HGS histology. However, unlike mutation, RAD51C and BRCA1 methylation were not associated with improved survival or greater sensitivity to platinum chemotherapy.
•Methylation and mutation of RAD51C or BRCA1 were mutually exclusive.•Methylation of BRCA1 was associated with younger age at diagnosis.•Germline BRCA1 mutations and BRCA1 methylation were associated with HGS histology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Mutations in the TP53 tumor suppressor gene are common in ovarian carcinoma (OC) but their impact on outcomes is controversial. We sought to define the relationship of TP53 mutations to cancer ...outcomes and their interactions with co-occurrent BRCA1 or BRCA2 (BRCA) mutations, comparing three different TP53 mutation classification schemes.
We performed next generation sequencing on 393 cases of OC prospectively followed for survival. TP53 mutations were classified according to three schemes termed Structural, Functional, and Hotspot. Mutation distribution was compared between cases with and without BRCA mutations. In a subset of 281 cases of high grade serous carcinoma (HGSC), overall survival was compared using Kaplan-Meier curves, logrank testing, and multivariate Cox regression analysis, both stratified and adjusted for BRCA mutation status. Multivariate logistic regression was used to analyze the effects of TP53 mutation type on platinum resistance.
TP53 mutations were identified in 76.8% of the total cohort (n = 302/393) and 87.9% of HGSC (n = 247/281). Cases with BRCA mutations demonstrated significantly higher TP53 mutation frequency overall (n = 84/91, 92.3% vs. n = 218/302, 72.2%, p < 0.001). TP53 mutations were not associated with overall survival, even when stratified by BRCA mutation. TP53 mutations were associated with platinum sensitivity, even after adjusting for BRCA mutation status (OR 0.41, p = 0.048). The choice of TP53 mutation classification scheme was not found to alter any significant outcome.
BRCA mutations significantly co-occur with TP53 mutations. After adjusting for BRCA mutations, TP53 mutations are associated with platinum sensitivity, and this effect is not dependent on TP53 mutation type.
•TP53 mutations were identified in 76.8% of ovarian carcinomas and 87.9% of high grade serous carcinomas in this cohort.•BRCA1 or BRCA2 mutations co-occur with TP53 mutations in ovarian carcinoma.•TP53 mutations are associated with platinum sensitivity, but not overall survival, in high grade serous ovarian carcinoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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