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Background: Recommendations for breast surveillance following breast plastic surgery are frequently changing. Establishing guidelines for long-term monitoring protocols may help identify treatable conditions and prevent untoward sequelae. We sought to evaluate the current state of evidence-based long-term monitoring protocols for patients following breast augmentation, reduction, and breast reconstruction., Methods: Official guidelines from various American societies and international societies were analyzed for alignment in evidence-based recommendations regarding breast surveillance., Results: The most recent US FDA update recommends magnetic resonance imaging or ultrasound starting 5-6 years after surgery and every 2-3 years thereafter. Discrepancies exist among professional societies: the American Society of Plastic Surgeons (ASPS) aligns with the FDA, while the American Society of Breast Surgeons and American College of Radiology (ACR) find no role for imaging for asymptomatic cases. Ultrasound is first-line for any implant concerns, with MRI if necessary. European societies oppose routine breast implant imaging. Breast reduction patients lack unique screening protocols; monitoring aligns with age and cancer risk factors. Following mastectomy and breast reconstruction, most organizations advocate for annual clinical examinations, with more frequent examinations initially. Evidence suggests that physical examination is sufficient to detect local cancer recurrence, with imaging only indicated if there is concern for recurrence. No surveillance imaging is recommended by the American Society of Clinical Oncology, National Comprehensive Cancer Network, or ASPS; however, ACR recommends mammography for autologous reconstruction only., Conclusion: Multispecialty and regulatory body alignment may promote provider and patient adherence. Ongoing studies of long-term outcomes are needed to strengthen the level of evidence for monitoring guidelines., (© 2024. The Author(s).)

It is thirty years since the BRCA1 and BRCA2 genes were discovered and genetic testing for BRCA1 and BRCA2 was introduced. Despite increasing awareness of the genetic basis of cancer and our evolving knowledge of effective means of prevention, screening, and treatment for hereditary breast and ovarian cancers, genetic testing is underutilized, and most mutation carriers remain unidentified. In this commentary, we explore possible reasons for why this might be so. Our focus is on factors that may influence or deter a patient from pursuing testing, rather than discussing the implications of receiving a positive test result. Issues of concern include an inadequate number of genetic counselors, restrictive (and conflicting) eligibility criteria for testing, the cost of the test, health insurance coverage, fear of future insurance discrimination, privacy issues, lack of familiarity with the testing process in primary care and gaps in both patient and provider knowledge about the impact and the value of testing. We discuss how these factors may lead to the underutilization of genetic testing in North America and throughout the world and discuss alternative models of genetic healthcare delivery. We have invited leaders in cancer genetic from around the world to tell us what they think are the barriers to testing in their host countries., (© 2024. The Author(s).)

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., Competing Interests: Conflict of Interest Brent Mabey, Elisha Hughes, Matthew Kucera, Timothy Simmons, Brooke Hullinger, Sarah Ratzel, Susanne Wagner, Jerry S. Lanchbury, Katherine Johansen Taber, Thomas P. Slavin, and Alexander Gutin were employed by Myriad Genetics, Inc. at the time of the study and received salaries and stocks as compensation. Holly J. Pederson and Monique Gary have received consulting fees from Myriad Genetics, Inc. Charis Eng has ownership interests in MyLegacy/MyFHH/Family Care Path. Judy Garber has received research funding from Ambry Genetics and Invitae and has other relationships, or an immediate family member with relationships, with AACR, Diana Helis Henry Medical Foundation, James P. Wilmot Foundation, Adrianne Helis Malvin Medical Research Foundation, Breast Cancer Research Foundation, Facing our Risk of Cancer Empowered, Novartis, GTx, Aleta BioTherapeutics, H3 Biomedicine, and Kronos Bio. Ora Gordon has had a consulting or advisory role with GRAIL and Genetic Technologies, has received travel or accommodation expenses from GRAIL, and has received research funding from GRAIL. Jennifer R. Klemp has received consulting fees and speakers’ bureaus fees from AstraZeneca, has ownership interests in Cancer Survivorship Training, is employed by Caris Life Sciences, Inc, and has received a salary as compensation and consulting fees. Olufunmilayo I. Olopade has an ownership interest in 54Gene and Tempus, has an ownership interest and has received a salary from CancerIQ, and has other interests in Color Genomics, Healthy Life for All Foundation, and Roche/Genetech. Mark E. Robson has provided clinical trial services to AstraZeneca and Merck and has received consulting fees from and/or been on advisory boards for Change Healthcare, Intellisphere, MyMedEd, Physician’s Education Resources, and Research to Practice. Pat W. Whitworth has received consulting fees from or had contracted research with Agendia, Biotheranostics, Genomic Health, Impedimed, Myriad Genetics, Inc, Prelude, and Veracyte, and has an ownership interest in Medneon. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest, (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

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., (© 2023. Society of Surgical Oncology.)

Over the past 30 years, genetic and epidemiological advances have revolutionised the prediction of breast cancer risk in women with significant family history. By screening these women for high- and intermediate-risk pathogenic variants and by interrogating their genomes for multiple lower-risk single-nucleotide polymorphisms (SNPs), we can provide individually tailored risk profiles in carriers of Mendelian breast cancer risk variants and in non-carriers, but clinical implementation of this approach is suboptimal. Risk mitigation may involve enhanced surveillance, preventive medications or risk-reducing surgery but barriers exist to the adoption of polygenic risk score (PRS)-based models in the clinic. PRS development has suffered from both systematic biases resulting from development and validation in those of European ancestry and from the consequences of unanticipated evolutionary differences particularly with regard to those of African ancestry. PRS approaches which take into account underlying genetic diversity offer a practical solution to the misapplication of European-derived PRS to other population groups including women of multiple ancestries. All ancestry PRS technology offers net benefit regardless of potency differences. While the new science of polygenics has surged ahead and its stratification insights have been incorporated into risk modelling, training of providers and genetic counsellors lags far behind and an educational revolution is also necessary to provide optimal patient care., (© 2023. The Author(s).)

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., (© 2023. Society of Surgical Oncology.)

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.

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., (Published by Elsevier Inc.)

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., Competing Interests: Financial disclosures/conflicts of interest: Holly Pederson serves as a consultant for Myriad Genetics, Inc. Pelin Batur has no financial disclosures or conflicts of interest., (Copyright © 2023 by The North American Menopause Society.)

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., (Copyright © 2022 The Cleveland Clinic Foundation. All Rights Reserved.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: In this ongoing case series, 33 genetic testing cases are documented in which tests were recommended, ordered, interpreted, or used incorrectly and/or in which clinicians faced challenges related to history/reports provided by patients or laboratories., Methods: An invitation to submit cases of challenges or errors in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, as part of a case series with Precision Oncology News, and via social media (i.e., Facebook, Twitter, LinkedIn). Deidentified clinical documentation was requested and reviewed when available. Thirty-three cases were submitted, reviewed, and accepted. A thematic analysis was performed. Submitters were asked to approve cases before submission., Results: All cases took place in the United States, involved hereditary cancer testing and/or findings in cancer predisposition genes, and involved medical-grade genetic testing, direct-to-consumer testing, or research genetic testing. In 9 cases, test results were misinterpreted, leading to incorrect screening or risk-reducing procedures being performed/recommended. In 5 cases, incorrect or unnecessary testing was ordered/recommended. In 3 cases, incorrect clinical diagnoses were made, or opportunities for diagnoses were delayed. In 3 cases, errors or challenges arose related to medical intervention after testing or reported genetic diagnosis. In 2 cases, physicians provided incorrect information related to the inheritance pattern of a syndrome. In 2 cases, there were challenges related to the interpretation of genetic variants. In 2 cases, challenges arose after direct-to-consumer testing. One case involved test results that should never have been reported based on sample quality. In 1 case, a patient presented a falsified test result. In 5 cases, multiple errors were made., Discussion: As genetic testing continues to become more complicated and common, it is critical that patients and nongenetics providers have access to accurate and timely genetic counseling information. Even as multiple medical bodies highlight the value of genetic counselors (GCs), tension exists in the genomics community as GCs work toward licensure and Medicare provider status. It is critical that health care communities leverage, rather than restrict, the expertise and experience of GCs so that patients can benefit from, and not be harmed by, genetic testing. In order to responsibly democratize genomics, it will be important for genetics and nongenetic health care providers to collaborate and use alternative service delivery models and technology solutions at point of care. To deliver on the promise of precision medicine, accurate resources and tools must be utilized., Competing Interests: Conflicts of Interest and Source of Funding: M.B.F., D.C.B., and E.T.M. are employed by My Gene Counsel (mGC), LLC. A.H. is a paid consultant of mGC. mGC is a digital genetic counseling company. For the remaining authors, none were declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

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.

Testing for hereditary predisposition to breast cancer is rapidly expanding in parallel with the emerging field of molecular genetics given the associated implications for screening, risk reduction and cancer therapeutics for identified gene mutation carriers. With the advent of next generation multigene panel testing for hereditary predisposition and decreasing cost for that testing, more breast cancer patients (and unaffected family members) are undergoing cancer genetic testing. With multiple genes being tested and the myriad of possible results and implications for patients and their families, the process of genetic counseling is of paramount importance in promoting understanding by both patients and providers of risks and options for risk management. Guidelines exist to facilitate a multidisciplinary approach to management of individuals identified as being at increased risk, and there must be an appreciation for flexibility as guidelines are applied to individual families. This update summarizes recommendations regarding who may benefit from breast cancer risk assessment and genetic counseling, controversies regarding inclusion for testing and provides a framework for the practical management of high risk gene carriers., Competing Interests: Conflicts of Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

Background: Bilateral nipple-sparing mastectomy (NSM) is a technically feasible operation and is associated with excellent cosmetic outcomes. The aim of this study was to evaluate trends in patient characteristics, indications for surgery and long-term outcomes of bilateral NSM for breast cancer risk reduction over time., Methods: A review of a single-centre experience with bilateral NSM performed between 2001 and 2017 for breast cancer risk reduction in patients without breast cancer was performed. Trends in patient characteristics and indications for surgery were evaluated over four time intervals: 2001-2005, 2006-2009, 2010-2013 and 2014-2017. Statistical analysis was performed using χ 2 tests., Results: Over the study period, 272 NSMs were performed in 136 patients; their median age was 41 years. The number of bilateral NSMs performed increased over time. The most common indication was a mutation in breast cancer-associated genes (104 patients, 76·5 per cent), which included BRCA1 (62 patients), BRCA2 (35), PTEN (2), TP53 (3) and ATM (2). Other indications were family history of breast cancer (19 patients, 14·0 per cent), lobular carcinoma in situ (10, 7·4 per cent) and a history of mantle irradiation (3, 2·2 per cent). The proportion of patients having a bilateral NSM for mutation in a breast cancer-associated gene increased over time (2001-2005: 2 of 12; 2006-2009: 9 of 17; 2010-2013: 34 of 41; 2014-2017: 61 of 66; P  < 0·001). Mean follow-up was 53 months; no breast cancers were found during follow-up., Conclusion: The use of bilateral NSM for breast cancer risk reduction is increasing and the indications have evolved over the past 16 years. These excellent long-term oncological results suggest that bilateral NSM is a good option for surgical breast cancer risk reduction.

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.

Background: With the advent of multigene panel testing for breast cancer patients, germline mutations with unknown association with cancer risk, known as variants of uncertain significance (VUS), are being increasingly identified. Some studies have shown higher rates of contralateral prophylactic mastectomies (CPM) in these patients, despite lack of evidence to support this intervention. We analyzed surgical choices in patients who were identified to have VUS., Study Design: A retrospective review was performed of patients with triple-negative breast cancer treated at a single institution after multigene panel tests became available (September 1, 2013 to February 28, 2017). Rates of genetic testing, results of testing, and surgical decision making were evaluated. Chi-square or Fisher's exact test was used to compare categorical variables. A p value <0.05 was considered statistically significant., Results: There were 477 triple-negative breast cancer patients identified; 331 met established criteria for genetic testing and 226 (68.3%) underwent genetic testing (multigene panel, n = 130 and BRCA1/2 testing, n = 96). All of them received risk-appropriate genetic counseling and follow-up. Of these, 29 (12.8%) patients had pathogenic mutations in BRCA1/2 or PALB2 (Mut+), 42 (18.6%) had VUS (VUS+), and 155 (68.6%) had no mutations identified (Mut-). Variants of uncertain significance in 6 of 42 patients (14.3%) were later reclassified as normal variants. Eighty-eight percent of Mut+ patients underwent CPM compared with 20.1% of Mut- and 21.4% of VUS+ patients (p < 0.001 for both). Rates of CPM were not significantly different between VUS+ and Mut- (p = 0.37). Multigene panel testing detected pathogenic mutations in non-breast cancer-associated genes in 6 patients, with significant management implications., Conclusions: When combined with risk-appropriate genetic counseling, detection of VUS did not lead to excessive CPM in this cohort of triple-negative breast cancer patients. Furthermore, panel testing detected mutations in non-breast cancer-associated genes, which had significant implications on management and outcomes., (Copyright © 2018 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

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., (© 2017 American Cancer Society.)

Background: Bilateral breast magnetic resonance imaging (MRI) is commonly used in the diagnostic workup of breast cancer (BC) to assess extent of disease and identify occult foci of disease. However, evidence for routine use of pre-operative MRI is lacking. Breast MRI is costly and can lead to unnecessary tests and treatment delays. Clinical care pathways (care paths) are value-based guidelines, which define management recommendations derived by expert consensus and available evidence based data. At Cleveland Clinic, care paths created for newly diagnosed BC patients recommend selective use of pre-operative MRI. We evaluated the number of pre-operative MRIs ordered before and after implementing an institution wide BC care paths in April 2014., Methods: A retrospective review was conducted of BC cases during the years 2012, 2014, and part of 2015. Patient, tumor and treatment characteristics were collected. Pre-operative MRI utilization was compared before and after care path implementation., Results: We identified 1,515 BC patients during the study period. Patients were more likely to undergo pre-operative MRI in 2012 than 2014 (OR: 2.77; P<0.001; 95% CI: 1.94-3.94) or 2015 (OR: 4.14; P<0.001; 95% CI: 2.51-6.83). There was a significant decrease in pre-operative MRI utilization between 2012 and 2014 (P<0.001) after adjustment for pre-operative MRIs ordered for care path indications., Conclusions: Implementation of online BC care paths at our institution was associated with a decreased use of pre-operative MRI overall and in patients without a BC care path indication, driving value based care through the reduction of pre-operative breast MRIs., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Hereditary syndromes that increase the risk of breast cancer are not common, but it is critical to recognize and manage them appropriately. This paper reviews the management of patients with the most common hereditary breast cancer syndromes, ie, hereditary breast and ovarian cancer syndrome, hereditary diffuse gastric cancer, Cowden syndrome (PTEN hamartoma tumor syndrome), Peutz-Jeghers syndrome, and Li-Fraumeni syndrome., (Copyright © 2016 Cleveland Clinic.)

Purpose: Breast magnetic resonance imaging (MRI) is accepted as a useful adjunct to screening mammography for women at high risk for breast cancer. Nevertheless, concerns about false-positive findings remain, and data about MRI harms and yields are limited. The aim of this study was to quantify harms and yields of breast MRI over time in a large series of patients., Methods: A retrospective review was performed of patients at increased risk for breast cancer who underwent annual screening digital mammography and MRI from 2007 to 2013. Harms were defined as events not producing a breast cancer diagnosis (ultrasonography [US], imaging-guided core or surgical biopsy procedure, recommendation for short-term follow-up, or a combination)., Results: Of 350 high-risk patients offered MRI screening, 320 underwent 757 screening MRI procedures over time. The median age at the first MRI was 48 years. All patients met American Cancer Society criteria for annual screening breast MRI. Total harms were highest with the first MRI procedure and decreased with subsequent MRI screening. Of 75 biopsy procedures performed, including 58 US- or MRI-guided core biopsy procedures and 17 surgical biopsy procedures, 6 specimens were found to be malignant, including 2 resulting from biopsy procedures performed based on findings from the first MRI scan, 0 from the second MRI scan, 3 from the third MRI scan, and 1 from the fourth MRI scan., Conclusion: Among women followed with screening MRI, the number of harms was shown to decrease over time. Breast cancer continued to be detected in MRI studies performed over time. This study demonstrates the utility of MRI screening performed over time in high-risk women., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Rabbit and human corneas were mounted in a specular microscope and perfused with a balanced salt solution of varying osmolality (200 to 500 mOsm). Measurements of corneal thickness were made throughout the perfusion period, and at selected times the corneas were fixed and prepared for scanning and transmission electron microscopy. A hypo-osmotic perfusion medium caused an increase in corneal thickness; by comparison, a hyperosmotic perfusion medium decreased corneal thickness in both rabbit and human corneas. Despite the marked changes in corneal thickness and the water movement that occurred across the endothelium, the cellular ultrastructure remained intact. In reversal studies (return to 300-mOsm perfusion medium), corneal thickness returned to control values with no marked changes in endothelial cell structure. These data indicate that the corneal endotheium can tolerate a wide range of solution osmolalities (200 to 400 mOsm) without marked endotheial cell breakdown if the essential ions are present.

Past studies have shown that apical junctional complexes (AJCs) of corneal endothelial cells break down in the presence of a Ca++-free medium. The purpose of this study was to examine the ability of Ca++ ionophores to maintain the AJCs in the Ca++-free media in both isolated perfused corneas and cultured endothelial cells. In addition, the ability of disintegrated AJCs to re-form when the endothelium is returned to a medium containing calcium ws also examined. Rabbit corneas were mounted in an in vitro specular microscope and perfused with a Ca++-free medium, or a Ca++-free medium containing 10(-5)M X537A or A23187 calcium ionophore. Also, confluent monolayer cultures of bovine corneal endothelial cells were placed in a Ca++-free medium or a Ca++-free medium containing 10(-5)M X537A or A23187 Ca++ ionophore and incubated for selected time periods. When junctional breakdown occurred, one cornea or culture plate was fixed for scanning and transmission electron microscopy (SEM and TEM), and the other was returned to a medium containing Ca++ and subsequently fixed for SEM and TEM. Both isolated perfused and cultured corneal endothelial cell AJCs exhibited marked disintegration in the presence of Ca++-free medium. The presence of an ionophore in the medium cultured cells. When returned to a medium containing Ca++, the corneas that had been perfused with Ca++-free medium containing an ionophore re-formed the junctions sooner than did those that had been perfused with a Ca++-free medium alone. These results suggests that the ionophores may be capable of mobilizing intracellular calcium to protect the AJCs.

While cardiac afferent nerve activity has been recorded from the ventrolateral (VLCN) and ventromedial (VMCN) cardiac nerves, left dorsal and ventral ansae subclaviae, and left upper thoracic white rami communicantes, little anatomical evidence for the existence of afferent fibers in these nerves has been reported. This study was designed to characterize the normal ultrastructure of the above nerves and to identify afferent fibers in them through Wallerian degeneration produced by dorsal root ganglionectomy. Laminectomies followed by dorsal root ganglionectomies were performed on left thoracic roots T1-T4 in six mongrel dogs. The nerves to be examined were removed from two animals at 1, 2, and 3 weeks following ganglionectomy and prepared for electron microscopy. Control nerves were obtained from two normal dogs. Degenerating nonmyelinated fibers were characterized by watery axoplasm containing clumps of electron-dense material. Degenerating myelinated fibers were distinguished by the separation of their myelin lamellae, producing characteristic whorls. After three weeks, afferent nonmyelinated axons had degenerated in all nerves, leaving only layered processes of Schwann cells in these areas. Approximately 5-15% of the fibers in each nerve degenerated, indicating their afferent nature. Of these fibers, 85-90% were nonmyelinated C fibers and the remainder myelinated Adelta fibers. These results indicate participation of both Adelta fibers and a large population of C fibers in transmission of cardiac afferent activity.

Uniformly severe corneal infections were produced in rabbits by intracorneal injection of a few viable Pseudomonas aeruginosa. The bacteria multiplied rapidly, and within 24 hr, about 10 million organisms were present. The numbers remained stable thereafter. Polymorphonuclear leukocytes (PMNs) began to infiltrate peripheral stroma 24 hr after inoculation. By 32 hr, ring-shaped dense accumulations of PMNs were apparent in the anterior stroma with moderate stromal edema. By 48 hr, the anterior one third of central stroma was severely involved with abscess formation and loss of epithelium, and PMNs had invaded full corneal thickness. The area of liquefactive necrosis eventually involved the entire cornea from limbus to limbus, and collagen staining was lost. Transmission electron microscopy revealed the accumulation of small electron-dense particles in association with collagen fibrils and degranulating PMNs.

Epithelial healing problems and basement membrane abnormalities have been observed in the corneas of patients with diabetes mellitus. In this study the rates of corneal epithelial wound healing following transcorneal freezing (with a 6-mm-diameter probe cooled in liquid nitrogen) were compared in diabetic (alloxan-induced) and nondiabetic rabbits. Also compared was the extent of injury to the epithelial basement membrane between the two groups. The overall rate of wound healing was faster in the diabetic animals; the wounds closed at 40 hours after freezing in diabetic animals and at 45 hours after in the nondiabetic controls. The lamina densa of the basement membrane was removed by the freezing procedure in two thirds of the diabetic animals but not in any of the controls. The results of this study indicate that epithelial healing problems in diabetes may be related to damage to the basement membrane, with resulting poor adhesion of regenerating epithelial cells.

Intracellular-reduced glutathione (GSH) was removed by thiol-oxidation with diamide during in vitro perfusion of the corneal endothelium. By 15 min the normal mosaic-like pattern of the endothelial cells was disrupted by serpentine-like lines of cell separation at the cell juntions. After 45 min of perfusion, infividual clusters of cells formed cup-shaped islands. The resultant exposure of Descemet's membrane to the perfusion solution resulted in corneal swelling. Transmission electron microscopy revealed that the endothelial cells separated at the apical junctions and that the microfilaments in the apical cytoplasm of cells formed dense bands, whereas the other subcellular organelles were normal in appearance. The change in cellular shape may be due to loss of cellular adhesion which results in the condensation of the microfilaments or contraction of the microfilaments. The addition of glucose to the perfusate prevented the diamide effect, and the diamide effect could be reversed upon removal and perfusion of a glutathione bicarbonate Ringer's solution. These results suggest that the ratio of reduced to oxidized glutathione in the endothelial cells plays a role in the maintenance of the endothelial cell barrier function.

After the intravenous injection of radioalbumin macroaggregate, large numbers of cytoplasmic inclusion bodies were observed in the lung tissue of rats. The inclusions were located mainly in the cytoplasm of type I alveolar lining cells, appeared 40 minutes after the injection, and lasted up to 2 days. These observations suggest that the type I alveolar lining cells participate in the clearing mechanism of the lung tissue, a function that thus far has not been attributed to this type of cell.