NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.

Personalized Breast Cancer Risk Assessment: Incorporation of Genetic and High-Risk Factorson Breast Cancer Risk and Management.

Breast cancer remains the second most diagnosed cancer in women worldwide and the number one cause of cancer in women in the United States. It is unfortunately the primary cause of cancerrelated deaths among women, with 14% of all cancer deaths attributed to it. Over the past decade, screening methods have matured, and imaging modalities are continuously improving. Screening mammograms remain the only modality that have been shown to improve breast cancer survival, however, more modalities like MRI, abbreviated MRI, and CT mammography are gaining in momentum. Now more than ever, providers need to identify the patient population that is at an elevated risk for breast cancer to offer them a personalized screening approach specific to their empiric risk. In this paper we shed light on risk factors of breast cancer and summarize risk assessment tools that have been recently incorporated in assessing a woman's risk of breast cancer. We also summarize new genetic testing strategies and their implications in prevention of breast cancer. And finally, we offer a personalized approach to management of women with agenetic predisposition as well as to women at elevated risk but without a genetic mutation. The hope is to identify women at increased risk and perfect a "personalized screening approach" for breast cancer.

Uptake of cancer risk management strategies among women who undergo cascade genetic testing for breast cancer susceptibility genes.

BACKGROUND: Uptake of cancer risk management based on inherited predispositions, which encompasses bilateral mastectomy (BLM), bilateral salpingo-oophorectomy (BSO), and intensified screening, is the primary motivation for cascade testing for hereditary breast and ovarian cancer (HBOC). However, long-term outcome data for cascade testers are lacking. METHODS: Medical records were abstracted for all unaffected women with pathogenic variants in HBOC genes from 2 cancer hospitals (2013-2019) with at least 1 year of follow-up to compare the uptake of surgery and screening between cascade and noncascade testers. RESULTS: Cascade testers (79.8%) were younger than noncascade testers (mean age, 37.6 vs 43.5 years; P = .002). Among women aged ≥40 years, 43% underwent BLM, and 71.6% underwent BSO, with no significant difference in uptake between cascade and noncascade testers. The mean time to BSO among cascade testers was shorter among women aged ≥40 years versus those aged <40 years (11.8 vs 31.9 months; P = .04); no such difference was observed among noncascade testers. Mammography and breast magnetic resonance imaging rates were low in the recorded 6 years for both groups after genetic counseling. CONCLUSIONS: Management uptake among cascade testers is high with rates comparable to those for unaffected BRCA-positive women. A large proportion of women act on cascade test results, and this represents a novel report of utilization of cancer management strategies.

The first BGICC consensus and recommendations for breast cancer awareness, early detection and risk reduction in low- and middle-income countries and the MENA region.

In low-middle income countries (LMICs) and the Middle East and North Africa (MENA) region, there is an unmet need to establish and improve breast cancer (BC) awareness, early diagnosis and risk reduction programs. During the 12th Breast, Gynecological & Immuno-oncology International Cancer Conference - Egypt 2020, 26 experts from 7 countries worldwide voted to establish the first consensus for BC awareness, early detection and risk reduction in LMICs/MENA region. The panel advised that there is an extreme necessity for a well-developed BC data registries and prospective clinical studies that address alternative modalities/modified BC screening programs in areas of limited resources. The most important recommendations of the panel were: (a) BC awareness campaigns should be promoted to public and all adult age groups; (b) early detection programs should combine geographically distributed mammographic facilities with clinical breast examination (CBE); (c) breast awareness should be encouraged; and (d) intensive surveillance and chemoprevention strategies should be fostered for high-risk women. The panel defined some areas for future clinical research, which included the role of CBE and breast self-examination as an alternative to radiological screening in areas of limited resources, the interval and methodology of BC surveillance in women with increased risk of BC and the use of low dose tamoxifen in BC risk reduction. In LMICs/MENA region, BC awareness and early detection campaigns should take into consideration the specific disease criteria and the socioeconomic status of the target population. The statements with no consensus reached should serve as potential catalyst for future clinical research.

Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy.

PURPOSE: This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance. PATIENTS AND METHODS: Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors. RESULTS: ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts. CONCLUSION: Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

Evaluation of BRCAPRO Risk Assessment Model in Patients with Ductal Carcinoma In situ Who Underwent Clinical BRCA Genetic Testing.

The authors retrospectively aimed to determine which of the following three scenarios, related to DCIS entry into BRCAPRO, predicted BRCA mutation status more accurately: (1) DCIS as an invasive breast cancer (IBC) entered using the actual age of diagnosis, (2) DCIS as IBC entered with 10 years added to the actual age of diagnosis, and (3) DCIS entered as no cancer. Of the 85 DCIS patients included in the study, 19% (n = 16) tested positive for a BRCA mutation, and 81% (n = 69) tested negative. DCIS patients who tested positive for a BRCA mutation had a higher BRCAPRO risk estimation (34.61%) than patients who tested negative (11.4%) when DCIS was entered at the actual age of diagnosis. When DCIS was entered with 10 years added to the actual age at diagnosis, the BRCAPRO estimate was still higher amongst BRCA positive patients (25.4%) than BRCA negative patients (7.1%). When DCIS was entered as no cancer, the BRCAPRO estimate remained higher among BRCA positive patients (2.56%) than BRCA negative patents (1.98%). In terms of accuracy of BRCA positivity, there was no statistically significant difference between DCIS at age at diagnosis, DCIS at 10 years later than age at diagnosis, and DCIS entered as no cancer (AUC = 0.77, 0.784, 0.75, respectively: p = 0.60). Our results indicate that regardless of entry approach into BRCAPRO, there were no significant differences in predicting BRCA mutation in patients with DCIS.

A two-stage approach to genetic risk assessment in primary care.

Genetic risk prediction models such as BRCAPRO are used routinely in genetic counseling for identification of potential BRCA1 and BRCA2 mutation carriers. They require extensive information on the counselee and her family history, and thus are not practical for primary care. To address this gap, we develop and test a two-stage approach to genetic risk assessment by balancing the tradeoff between the amount of information used and accuracy achieved. The first stage is intended for primary care wherein limited information is collected and analyzed using a simplified version of BRCAPRO. If the assessed risk is sufficiently high, more extensive information is collected and the full BRCAPRO is used (stage two: intended for genetic counseling). We consider three first-stage tools: BRCAPROLYTE, BRCAPROLYTE-Plus, and BRCAPROLYTE-Simple. We evaluate the two-stage approach on independent clinical data on probands with family history of breast and ovarian cancers, and BRCA genetic test results. These include population-based data on 1344 probands from Newton-Wellesley Hospital and mostly high-risk family data on 2713 probands from Cancer Genetics Network and MD Anderson Cancer Center. We use discrimination and calibration measures, appropriately modified to evaluate the overall performance of a two-stage approach. We find that the proposed two-stage approach has very limited loss of discrimination and comparable calibration as BRCAPRO. It identifies a similar number of carriers without requiring a full family history evaluation on all probands. We conclude that the two-stage approach allows for practical large-scale genetic risk assessment in primary care.

American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.

The American Society of Clinical Oncology (ASCO) has long affirmed that the recognition and management of individuals with an inherited susceptibility to cancer are core elements of oncology care. ASCO released its first statement on genetic testing in 1996 and updated that statement in 2003 and 2010 in response to developments in the field. In 2014, the Cancer Prevention and Ethics Committees of ASCO commissioned another update to reflect the impact of advances in this area on oncology practice. In particular, there was an interest in addressing the opportunities and challenges arising from the application of massively parallel sequencing-also known as next-generation sequencing-to cancer susceptibility testing. This technology introduces a new level of complexity into the practice of cancer risk assessment and management, requiring renewed effort on the part of ASCO to ensure that those providing care to patients with cancer receive the necessary education to use this new technology in the most effective, beneficial manner. The purpose of this statement is to explore the challenges of new and emerging technologies in cancer genetics and provide recommendations to ensure their optimal deployment in oncology practice. Specifically, the statement makes recommendations in the following areas: germline implications of somatic mutation profiling, multigene panel testing for cancer susceptibility, quality assurance in genetic testing, education of oncology professionals, and access to cancer genetic services.

Genetic risk assessment for breast and gynecological malignancies.

PURPOSE OF REVIEW: Breast cancer and gynecological cancers impact a significant portion of women each year. Identifying women at high risk is essential for implementation of screening and risk reduction recommendations. Risk assessment for these cancers involves an evaluation of many factors. This review discusses an overview of hereditary breast and gynecological cancers and the process of a cancer genetic risk assessment. RECENT FINDINGS: Risk assessment models for breast cancer should be used with caution, especially in populations in which they are not validated. Additionally, the BRCAPRO model may underestimate the likelihood of BRCA mutations in certain populations.The utilization of next-generation sequencing panels is increasing. Benefits and limitations of panel testing are described in the literature. There are currently no guidelines for the use of panel testing; however, some reports of institutional experiences and recommendations are available. SUMMARY: Cancer genetic risk assessment is complex, and models developed to estimate risk may not apply to all populations. Identifying genetic factors related to cancer risk is also becoming increasingly complex with the clinical implementation of panel testing. This testing approach should be critically evaluated by healthcare providers. Further research is needed to create evidence-based guidelines for panel testing and management recommendations for moderately penetrant genes.

Ecological momentary assessment of sleep, symptoms, and mood during chemotherapy for breast cancer.

OBJECTIVE: This study examined the association of sleep before and during a chemotherapy (CT) cycle for breast cancer with symptoms and mood during a CT cycle. METHODS: Twenty women undergoing CT for breast cancer completed the Pittsburgh Sleep Quality Index (PSQI) 1 h prior to a CT infusion. For 3 weeks following infusion, participants estimated sleep efficiency, minutes to sleep (sleep latency), number of nocturnal awakenings (sleep fragmentation (SF)), and sleep quality (SQ) each morning and rated symptoms (nausea, fatigue, numbness, and difficulty thinking) and mood three times daily (morning, afternoon, and evening) via ecological momentary assessments using automated handheld computers. RESULTS: The results showed that disturbed sleep (PSQI score > 5) prior to CT infusion was associated with greater fatigue, and more negative and anxious mood throughout the 3-week CT cycle, and good pre-CT infusion sleep (PSQI score < 5) buffered anxious mood in the first days following infusion. Time-lagged analyses controlling for mood/symptom ratings reported the previous evening revealed that longer sleep latency and greater SF were associated with greater daytime fatigue; poorer SQ and greater SF were antecedents of worse morning negative mood, and greater SF was associated with feeling more passive and drowsy. No evening symptom or mood ratings were related to subsequent SQ. CONCLUSIONS: These findings suggest that disturbed sleep before and after a CT infusion exacerbates fatigue, and negative, anxious, and drowsy mood during a CT cycle. Reducing sleep disturbance may be an important way to improve quality of life during CT.

Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes.

Preimplantation genetic diagnosis (PGD) allows couples to avoid having a child with an inherited condition, potentially reducing cancer burden in families with a hereditary cancer predisposition. This study investigated and compared awareness and acceptance of PGD among patients with different hereditary cancer syndromes. Questionnaires were mailed to 984 adults with hereditary breast and ovarian cancer, Lynch syndrome, familial adenomatous polyposis, or multiple endocrine neoplasia type 1 or 2. Associations between clinical, demographic, and psychosocial factors and awareness and acceptance of PGD were examined. Of 370 respondents (38 % return rate), 28 % felt their syndrome impacted family planning, 24 % were aware of PGD, 72 % felt that PGD should be offered, 43 % would consider using PGD, and 29 % were uncertain. Family experience and syndrome-specific characteristics, such as disease severity, quality of life and availability of medical interventions as well as gender, family planning stage, and religiosity impact perceptions of the acceptability of PGD, though a high level of uncertainty exists. Hereditary cancer patients lack awareness of PGD despite feeling that PGD should be offered, highlighting the need for education on this topic. While we found attitudes about the acceptability of PGD to be generally similar to those reported in the literature and of genetics and ethics experts, we observed similarities and differences between syndromes that provide insight into why some hereditary cancer patients may find PGD more acceptable than others.

Clinical assessment of breast cancer risk based on family history.

Family history is a key component of breast cancer risk assessment. Family history provides clues as to the likelihood of a hereditary breast cancer syndrome and the need for a cancer genetics referral and can be used in the setting of a breast cancer risk assessment model to estimate a woman's risk. Appropriate breast cancer screening and risk reduction management plans rely on an accurate assessment of a patient's family history. This article reviews the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer Risk Reduction and provides insight into the application of the guidelines in clinical practice.

Expanding the criteria for BRCA mutation testing in breast cancer survivors.

PURPOSE: Every year approximately 25% of women diagnosed with breast cancer are younger than 50 years of age, and almost 10% of them have a BRCA mutation. Not all potential carriers are identified by existing criteria for BRCA testing. We estimated the costs and benefits of different BRCA testing criteria for women with breast cancer younger than 50 years. METHODS: We developed a Markov Monte Carlo simulation to compare six criteria for BRCA mutation testing: (1) no testing (reference); (2) medullary breast cancer in patients younger than 50 years; (3) any breast cancer in patients younger than 40 years; (4) triple negative (TN) breast cancer in patients younger than 40 years; (5) TN breast cancer in patients younger than 50 years; (6) any breast cancer in patients younger than 50 years. Net health benefits were life expectancy and quality-adjusted life expectancy, and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of new breast and ovarian cancer cases. RESULTS: BRCA mutation testing for all women with breast cancer who were younger than 50 years could prevent the highest number of breast and ovarian cancer cases, but with unfavorable ICERs. Testing women with TN breast cancers who were younger than 50 years was cost-effective with an ICER of $8,027 per year of life gained ($9,084 per quality-adjusted life-year), and could reduce subsequent breast and ovarian cancer risks by 23% and 41%, respectively, compared with the reference strategy. CONCLUSION: Testing women with TN breast cancers who were younger than 50 years for BRCA mutations is a cost-effective strategy and should be adopted into current guidelines for genetic testing.

Clinical application of breast cancer risk assessment models.

With the evolving availability of testing for genetic cancer syndromes, oncologists now are increasingly expected to review family histories and to give a genetic risk assessment as part of their care for breast cancer. The most important of these breast cancer genetic syndromes identified to date have been those associated with the BRCA1 and BRCA2 genes. Therefore, the proper identification of potentially affected families and providing risk assessment estimates will be ever more essential. This review outlines several different available breast cancer risk assessment models. Risk models for the development of breast cancer as well as risk models that estimate the chance of having a genetic cancer syndrome are discussed. Their clinical applications are also outlined and clinical situations appropriate for each model are reviewed.

Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007.

A consensus conference including thirty experts was held in April, 2007, to discuss risk factors for breast cancer and their management. Four categories of risk were outlined, from breast cancer "average" through "very high" risk, the latter including individuals with high penetrance BRCA1/2 gene mutations. Guidelines for management of patients in each of these categories were discussed, with the major portion of the conference being devoted to individuals with BRCA1/2 mutations. Prevalence of these mutations in the general populations was estimated to be 1 in 250-500 individuals, with an increased prevalence in Ashkenazic Jews and other founder groups. Risk reduction strategies for these individuals include surveillance, with or without chemoprevention drugs, or surgical procedures to remove the organs at risk, i.e., bilateral mastectomy and/or bilateral salpingo-oophorectomy. These risk reduction strategies were evaluated fully, and recommendations were made for the care of patients in each of the risk categories. These guidelines for patient care were approved by the entire group of experts.

BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model.

PURPOSE: The BRCAPRO model, used to predict a family's likelihood of carrying a BRCA1 or BRCA2 mutation, was designed using mutation frequencies of white and Ashkenazi Jewish populations, and may not be applicable to other populations. BRCAPRO was recently validated in African Americans, although has yet to be examined in Hispanics. This retrospective study reports the mutation frequency and spectrum of BRCA1 and BRCA2 mutations in a Hispanic population and evaluates the BRCAPRO model in Hispanics. PATIENTS AND METHODS: A descriptive analysis of mutation frequency and spectrum was performed for Hispanic patients who underwent BRCA1 and BRCA2 genetic testing at a single institution. For comparative analysis of the BRCAPRO risk model, Hispanic patients who underwent comprehensive analysis were compared with white controls using area under the receiver operating characteristic curves (AUROC). RESULTS: Fourteen Hispanic individuals who underwent comprehensive analysis were identified to carry a mutation in BRCA1 or BRCA2 (17.9%; 95% CI, 10.2% to 28.3%) and seven individuals had a variant of uncertain significance (9.0%; 95% CI, 12.0% to 30.8%). A total of eight different mutations and three variants were observed within the entire Hispanic population. When evaluating the performance of the BRCAPRO model, the AUROC for Hispanics was 0.774 (95% CI, 0.63 to 0.90), compared with the AUROC of 0.770 (95% CI, 0.65 to 0.89) for whites. CONCLUSION: Deleterious BRCA1 and BRCA2 mutations occur at considerable frequency within the Hispanic population, many of which have been identified previously in other ethnic populations. The BRCAPRO model appears to perform equally well in Hispanics as in whites.

Ductal lavage and risk assessment of breast cancer.

Following recent advances in breast cancer chemoprevention, much emphasis has been placed on risk assessment to evaluate whether women at increased risk for developing breast cancer should proceed with breast cancer risk reduction strategies. The currently available risk-reduction approaches include screening, chemoprevention, and preventive surgeries. Breast cancer arises from the epithelial linings of the ductal system, and it is believed that hyperplasia and atypical hyperplasia represent early changes in the breast carcinogenesis process. The ductal lavage procedure offers a minimally invasive method to obtain breast epithelial cells from the ductal system for cytopathologic analysis to provide individualized risk assessment. This paper reviews breast cancer risk factors, with an emphasis on cytological atypia and the role of ductal lavage in breast cancer risk assessment.