Validation of a clinical breast cancer risk assessment tool combining a polygenic score for all ancestries with traditional risk factors.

PURPOSE: We previously described a combined risk score (CRS) that integrates a multiple-ancestry polygenic risk score (MA-PRS) with the Tyrer-Cuzick (TC) model to assess breast cancer (BC) risk. Here, we present a longitudinal validation of CRS in a real-world cohort. METHODS: This study included 130,058 patients referred for hereditary cancer genetic testing and negative for germline pathogenic variants in BC-associated genes. Data were obtained by linking genetic test results to medical claims (median follow-up 12.1 months). CRS calibration was evaluated by the ratio of observed to expected BCs. RESULTS: Three hundred forty BCs were observed over 148,349 patient-years. CRS was well-calibrated and demonstrated superior calibration compared with TC in high-risk deciles. MA-PRS alone had greater discriminatory accuracy than TC, and CRS had approximately 2-fold greater discriminatory accuracy than MA-PRS or TC. Among those classified as high risk by TC, 32.6% were low risk by CRS, and of those classified as low risk by TC, 4.3% were high risk by CRS. In cases where CRS and TC classifications disagreed, CRS was more accurate in predicting incident BC. CONCLUSION: CRS was well-calibrated and significantly improved BC risk stratification. Short-term follow-up suggests that clinical implementation of CRS should improve outcomes for patients of all ancestries through personalized risk-based screening and prevention.

Young Black Women May be More Likely to Have First Mammogram Cancers: A New Perspective in Breast Cancer Disparities.

INTRODUCTION: Black women are diagnosed with breast cancer at earlier ages and are 42% more likely to die from the disease than White women. Recommendations for commencement of screening mammography remain discordant. This study sought to determine the frequency of first mammogram cancers among Black women versus other self-reported racial groups. METHODS: In this retrospective cohort study, clinical and mammographic data were obtained from 738 women aged 40-45 years who underwent treatment for breast cancer between 2010 and 2019 within a single hospital system. First mammogram cancers were defined as those with tissue diagnoses within 3 months of baseline mammogram. Multivariate logistic regression was applied to assess variables associated with first mammogram cancer detection. RESULTS: Black women were significantly more likely to have first mammogram cancer diagnoses (39/82, 47.6%) compared with White women (162/610, 26.6%) and other groups (16/46, 34.8%) [p < 0.001]. Black women were also more likely to have a body mass index > 30 (p < 0.001), higher clinical T categories (p = 0.02), and present with more advanced clinical stages (p = 0.03). Every month delay in mammographic screening beyond age 40 years (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.05-1.07; p < 0.0001), Black race (OR 2.24, 95% CI 1.10-4.53; p = 0.03), and lack of private insurance (OR 2.41, 95% CI 1.22-4.73; p = 0.01) were associated with an increased likelihood of cancer detection on first mammogram. CONCLUSION: Our findings suggests that Black women aged 40-45 years may be more likely to have cancer detected on their first mammogram and would benefit from starting screening mammography no later than age 40 years, and for those with elevated lifetime risk, even sooner.

A Randomized Trial Comparing the Effectiveness of Pre-test Genetic Counseling Using an Artificial Intelligence Automated Chatbot and Traditional In-person Genetic Counseling in Women Newly Diagnosed with Breast Cancer.

BACKGROUND: Alternative service delivery models are critically needed to address the increasing demand for genetics services and limited supply of genetics experts available to provide pre-test counseling. METHODS: We conducted a prospective randomized controlled trial of women with stage 0-III breast cancer not meeting National Comprehensive Cancer Network (NCCN) criteria for genetic testing. Patients were randomized to pre-test counseling with a Chatbot or a certified genetic counselor (GC). Participants completed a questionnaire assessing their knowledge of breast cancer genetics and a survey assessing satisfaction with their decision regarding pre-test counseling. RESULTS: A total of 39 patients were enrolled and 37 were randomized to genetic counseling with an automated Chatbot or a GC; 19 were randomized to Chatbot and 18 to traditional genetic counseling, and 13 (38.2%) had a family member with breast cancer but did not meet NCCN criteria. All patients opted to undergo genetic testing. Testing revealed six pathogenic variants in five patients (13.5%): CHEK2 (n = 2), MSH3 (n = 1), MUTYH (n = 1), and BRCA1 and HOXB13 (n = 1). No patients had a delay in time-to-treatment due to genetic testing turnaround time, nor did any patients undergo additional risk reducing surgery. There was no significant difference in median knowledge score between Chatbot and traditional counseling (11 vs. 12, p = 0.09) or in median patient satisfaction score (30 vs. 30, p = 0.19). CONCLUSION: Satisfaction and comprehension in patients with breast cancer undergoing pre-test genetic counseling using an automated Chatbot is comparable to in-person genetic testing. Utilization of this technology can offer improved access to care and a much-needed alternative for pre-test counseling.

Care after premenopausal risk-reducing salpingo-oophorectomy in high-risk women: Scoping review and international consensus recommendations.

Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease.

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

Management of genitourinary syndrome of menopause in female cancer patients: a focus on vaginal hormonal therapy.

Genitourinary syndrome of menopause is a condition describing the hypoestrogenic effects on the female genitals and lower urinary tract leading to symptoms such as vaginal dryness, vulvar and vaginal burning, dyspareunia and dysuria. Genitourinary syndrome of menopause is experienced by over half of postmenopausal women, and is even more pervasive in women with cancer. Due to treatments such as surgery, chemotherapy, radiation, and hormonal therapy, women may experience early menopause resulting in earlier and more severe symptoms. Understanding the scope of this issue in female breast and gynecologic cancer survivors and identifying treatment options for this complex patient population are paramount. Tailored patient treatments include nonhormonal therapies (vaginal moisturizers, lubricants, pelvic floor physical therapy, dilator therapy, counseling), systemic and local hormonal therapies. Consensus recommendations by medical societies and associated evidence are reviewed, with emphasis on safety and efficacy of local vaginal hormonal therapies, and management variations noted depending on cancer type and characteristics. With knowledge and understanding of the unmet need associated with under-recognition and under-treatment of genitourinary syndrome of menopause, providers caring for women with cancer are in a position to improve the quality of life of their patients by providing safe and effective treatments.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

Practical Cancer Genetics and Genomics in Women's Health.

There have been rapid advances in precision medicine since the Human Genome Project was completed in 2003, including several noteworthy advances in Women's Health. This includes significant advances in predicting individualized cancer risk based on hereditary cancer genetic testing, with the number of known cancer-predisposition genes extending well beyond BRCA1 and BRCA2. This has been coupled with gene-specific management guidelines for several gynecologic cancers. In addition, genetic testing can also inform therapy selection for women with gynecologic cancers. Here we address hereditary cancer and practical cancer genetics as it relates to the practicing Obstetrician/Gynecologist.

Breast cancer risk associated with atypical hyperplasia and lobular carcinoma in situ initially diagnosed on core-needle biopsy.

BACKGROUND: Breast cancer risk estimates for atypical lesions are based primarily on case-control studies of patients with open biopsies. The authors report the cumulative breast cancer incidence after a core biopsy diagnosis of atypical hyperplasia (ductal or lobular) or lobular carcinoma in situ. METHODS: A cohort study with central pathology review was conducted on 393 patients who had core biopsy diagnoses of atypical hyperplasia and lobular carcinoma in situ from 1995 through 2010. Follow-up was available for 255 of 264 patients (97%) at a median of 87 months (range, 3-236 months). RESULTS: There were 212 patients (54%) who were not upgraded on excision and had no personal history of breast cancer. Of these, 21 of 212 (9.9%) developed breast cancer, including 15 invasive carcinomas, 4 ductal carcinomas in situ, 1 pleomorphic lobular carcinoma in situ, and 1 unknown type. The prior core biopsy diagnoses were atypical ductal hyperplasia for 11 patients (52%) and atypical lobular hyperplasia/lobular carcinoma in situ in the remaining 10 patients (48%). The number of atypical foci in the core biopsy was not significantly associated with the subsequent development of breast cancer (P = .42). Of the 15 invasive carcinomas, 11 (73%) were ipsilateral, 11 (73%) were pathologic T1 tumors, 5 (33%) were pathologic N1 tumors, 13 (87%) were estrogen receptor-positive, and 1 (7%) was amplified for human epidermal growth factor receptor 2. CONCLUSIONS: In patients who had an initial diagnosis of atypical hyperplasia or lobular carcinoma in situ on core biopsy, the 7-year cumulative breast cancer incidence was 9.9%. Most tumors were ipsilateral, stage I, estrogen receptor-positive, invasive carcinomas. The current data support close clinical and radiologic follow-up for more than 5 years in this patient population. Cancer 2018;124:459-65. © 2017 American Cancer Society.

Impact of an embedded genetic counselor on breast cancer treatment.

BACKGROUND: We predicted that embedding a genetic counselor within our breast practice would improve identification of high-risk individuals, timeliness of care, and appropriateness of surgical decision making. The aim of this study is to compare cancer care between 2012 and 2014, prior to embedding a genetic counselor in the breast center and following the intervention, respectively. METHODS: A retrospective review of patients diagnosed with breast cancer in 2012 (n = 471) and 2014 (n = 440) was performed to assess patterns of medical genetics referral, compliance with referral, genetic testing findings, and impact on treatment. RESULTS: Between 2012 and 2014, patients were 49% more likely to be referred to genetics, 66% more likely to follow through with their genetic counseling appointment, experienced a 73% reduction in wait times to genetic counseling visits and 69% more likely to have genetic testing results prior to surgery. Notably, while the number of genetic mutations identified was in the expected range over both time periods (9% of those tested in 2012 vs. 6.6% of those tested in 2014), there was a 31% reduction in time to treatment in 2014 vs. 2012. CONCLUSION: Awareness of germline genetic mutations is critical in surgical decision making for newly diagnosed breast cancer patients. Having an experienced genetics specialist on site in a busy surgical breast clinic allows for timely access to genetic counseling and testing, and may have influenced time to treatment in our institution.

Racial disparities in breast cancer risk factors and risk management.

Racial disparities in breast cancer outcomes are well described across the spectrum of screening, diagnosis, treatment, and survivorship. Breast cancer mortality is markedly elevated for Non-Hispanic Black women compared with other racial and ethnic groups, with multifactorial causes. Here, we aim to reduce this burden by identifying disparities in breast cancer risk factors, risk assessment, and risk management before breast cancer is diagnosed. We describe a reproductive profile and modifiable risk factors specific to the development of triple-negative breast cancer. We also propose that screening strategies should be both risk- and race-based, given the prevalence of early-onset triple-negative breast cancer in young Black women. We emphasize the importance of early risk assessment and identification of patients at hereditary and familial risk and discuss indications for a high-risk referral. We discuss the subtleties following genetic testing and highlight "uncertain" genetic testing results and risk estimation challenges in women who test negative. We trace aspects of the obesity epidemic in the Black community to infant feeding patterns and emphasize healthy eating and activity. Finally, we discuss building an environment of trust to foster adherence to recommendations, follow-up care, and participation in clinical trials. Addressing relevant social determinants of health; educating patients and clinicians on factors impacting disparities in outcomes; and encouraging participation in targeted, culturally sensitive research are essential to best serve all communities.

Use of exogenous hormones in those at increased risk for breast cancer: contraceptive and menopausal hormones in gene carriers and other high-risk patients.

IMPORTANCE AND OBJECTIVE: Addressing the hormonal needs of individuals at increased risk of breast cancer (BC) can be a challenge. Observational, prospective, and case-control data support the safety of hormonal contraception in women, often with the added benefits of ovarian and endometrial cancer risk reduction. The majority of data on menopausal hormone therapy (HT) in the highest-risk patients comes from studies of patients with pathogenic variants in BRCA1 and BRCA2 who undergo early surgical menopause. The benefits of risk-reducing salpingo-oophorectomy are not minimized by HT, whereas its use mitigates accelerated osteoporosis and cardiovascular disease. In other patients at increased risk, such as with family history, studies have shown little risk with significant benefit. METHODS: We review evidence to help women's health practitioners aid patients in making choices. The paper is divided into four parts: 1, contraception in the very high-risk patient (ie, with a highly penetrant BC predisposition gene); 2, contraception in other patients at increased risk; 3, menopausal HT in the gene carrier; and 4, HT in other high-risk patients. DISCUSSION AND CONCLUSION: Women at increased risk for BC both early and later in life should be offered reassurance around the use of premenopausal and postmenopausal hormone therapies. The absolute risks associated with these therapies are low, even in the very high-risk patient, and the benefits are often substantial. Shared decision making is key in presenting options, and knowledge of the data in this area is fundamental to these discussions.

Comprehensive Care of Women With Genetic Predisposition to Breast and Ovarian Cancer.

Women at risk for hereditary breast and ovarian cancer syndromes are frequently seen in primary care and gynecology clinics. They present with a distinctive set of clinical and emotional needs that revolve around complex risk management discussions and decision making. The care of these women calls for the creation of individualized care plans that facilitate adjustment to the mental and physical changes associated with their choices. This article provides an update on comprehensive evidence-driven care of women with hereditary breast and ovarian cancer. The aim of this review is to aid clinicians in identifying those at risk for hereditary cancer syndromes and provide practical advice on patient-centered medical and surgical risk management. Topics of discussion include enhanced surveillance, preventive medications, risk-reducing mastectomy and reconstruction, risk-reducing bilateral salpingo-oophorectomy, fertility, sexuality, and menopausal management, with attention to the importance of psychological support. High-risk patients may benefit from a multidisciplinary team that provides realistic expectations with consistent messaging. The primary care provider must be aware of the special needs of these patients and the consequences of their risk management interventions.

Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants.

Importance: Identifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD). Objective: To evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS. Design, Setting, and Participants: Prospective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023. Exposures: Review of physical and electronic medical records, and follow-up through clinical visits or telephone interviews. Main Outcomes and Measures: Lifetime cancer risks in PHTS relative to the general population. Results: A total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P < .001) of thyroid (age-adjusted standardized incidence ratios [SIR], 32.1; 95% CI, 26.0-39.0), kidney (SIR, 26.5; 95% CI, 18.8-36.3), endometrial (SIR, 26.0; 95% CI, 19.5-34.1), breast (SIR, 20.3; 95% CI, 17.3-23.7), and colorectal (SIR, 7.9; 95% CI, 5.2-11.7) cancers, and melanoma (SIR, 6.3; 95% CI, 3.5-10.5) were observed. Of the 341 patients with PHTS with cancer, 51 (15%) had 1 or more cancers diagnosed at age 29 years or younger, and 16 (31.4%) of those developed SMN at final follow-up. Twenty-three patients with PHTS with NDD and cancer were identified, with 5 (22%) having developed SMN at final follow-up. Individuals with PHTS and NDD showed higher lifetime cancer risks compared with individuals with PHTS but without NDD (hazard ratio, 2.7; 95% CI, 1.7-4.2; P < .001). Conclusions and Relevance: This cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.

Reducing the risk of breast cancer.

Breast cancer remains the most common female malignancy in the United States. Reducing this cancer burden involves identification of high-risk individuals and personalized risk management. Because coronary artery disease remains the primary cause of death for women, any intervention to reduce breast cancer risk must be weighed against comorbidities and interventions affecting cardiovascular risk reduction. For select women at increased risk for breast cancer, preventive medication can greatly decrease risk and is vastly underutilized. Women's health clinicians are poised to evaluate risk, promote breast cancer risk reduction, and manage overall health.

Twenty-two-year evolution of a Medical Breast Service: Filling the important gaps between breast surgery and medical oncology.

BACKGROUND: Historically, surgeons have provided subspecialty breast care. The development of a robust medical breast program in a large academic center staffed by trained primary care providers initially showed a shift in care of benign breast disease away from surgeons. In this review, we aim to revisit the practice after 20 years. Medical patients are defined as patients with symptomatic issues (eg, pain or lump), those at increased risk (due to family history, genetic mutations, or benign atypical lesions), or survivors in need of long-term care. METHODS: Data for this review were collected retrospectively from an internal outpatient appointment dataset. The sample included data for 3 staff breast surgeons (2.6 clinical full-time employees [FTEs]), 3 staff medical breast physicians (2.4 clinical FTEs), and 2 medical breast advanced practice providers (2.0 clinical FTEs). Provider visit types were grouped into 1 of 4 categories (new medical, established medical, new surgical, and established surgical) in order to review the percentages of outpatient visits by provider group. RESULTS: Before the institution of the Medical Breast Service, 75% of breast surgeons' outpatient visits were for either new or established medical issues. Our most recent analyses show that between 2013 and 2017 breast surgeons averaged 19% of surgical outpatient visits for medical issues. Higher surgical outpatient visits have resulted in higher surgical volume, increased surgical productivity and time spent in the operating room, and decreased time to treatment at our institution. Both surgical and medical breast providers can be added and become rapidly productive with focus on their respective areas of expertise. CONCLUSION: The Medical Breast Service has met its expectations in providing access for symptomatic patients, personalized care for those at risk, and attentive care to long-term survivors. The program has allowed for surgeons to focus on surgical outpatient visits, driving surgical volume and productivity, and streamlining care.

Controversies in Hereditary Cancer Management.

Personalized management of patients at risk ideally should involve a multidisciplinary team of not only genetic counselors and surgeons, but also women's health or menopause specialists, knowledgeable psychologists, and primary care providers or obstetrician-gynecologists aware of the risks and fears "previvors" (survivors of a predisposition to cancer who have not had the disease) face as well as the issues that are common postoperatively. Identification of patients at risk for hereditary cancer, understanding of current genetic testing modalities and potential results, knowledge about screening and prevention including timing of surveillance, preventive medication and risk-reducing surgeries, understanding limitations and comorbidities associated with these risk management strategies and long-term psychological support are all important in hereditary cancer management. We describe issues surrounding the identification of the high-risk patient, universal testing in breast and ovarian cancer, and testing in special populations. We describe a simplified approach to understanding and communicating genetic testing results and nuances of testing including direct-to-consumer testing. We highlight concerns surrounding breast cancer screening during pregnancy and lactation. A framework for practical management and counseling of women who opt for risk-reducing salpingo-oophorectomy or risk-reducing mastectomy or both is provided. We provide an in-depth discussion of questions that arise in relation to timing of surgery, fertility preservation, management of menopausal symptoms, and surgical technique. Alternative choices in women who choose to delay bilateral salpingo-oophorectomy are reviewed. Finally, the psychosocial effects of carrying a genetic mutation and the issues that women face when undergoing to risk-reducing surgery including adjustment, sexuality issues, and cosmesis are addressed.