Racial Disparities in Breast Cancer Genetic Testing May be Mitigated by Counseling.

BACKGROUND: Currently, racial disparities exist in access to genetic testing. Recent developments have helped narrow the gap in accessibility. The purpose of this study was to determine whether racial disparities in genetic consultation attendance and completion of genetic testing persist, and, if so, factors that contribute to under-utilization of these resources. METHODS: A single-institution retrospective review of breast patients referred for genetic counseling between 2017 and 2019 was performed. Univariate and multivariate logistic regression evaluated factors associated with genetic counseling attendance and genetic testing. RESULTS: A total of 596 patients were referred for genetic counseling: 433 (72.7%) white; 138 (23.2%) black; and 25 (4.2%) other or unknown. In multivariate analysis, black patients, patients without breast cancer family history, and patients without a current cancer diagnosis, classified as high risk, were significantly less likely to attend their genetics appointment (p = 0.010, p = 0.007, p = 0.005, respectively). Age, insurance type, distance from facility, and need for chemotherapy did not significantly impact consult completion rate. Of the patients who completed a genetic consult, 84.4% (n = 248) had genetic testing and 17.7% (n = 44) had a pathogenic variant. For patients who attended counseling, there were no significant factors that were predictive with receipt of genetic testing. CONCLUSIONS: In this study, there was a significant association between race and attending genetic counseling. Once counseled, most patients went on to receive genetic testing, and racial disparities in testing disappeared, emphasizing the value of providing additional education about the importance and purpose of genetic testing.

Mainstreamed genetic testing of breast cancer patients: experience from a single surgeon's practice in a large US Academic Center.

This study evaluated the impact of mainstreamed genetic testing (MGT) on the timing and uptake of testing in an academic breast surgeon's practice. Before September 2019 (pre-MGT phase), a breast surgery practice at Massachusetts General Hospital followed a traditional model of a pre-test consultation with a genetic counselor (GC) following a referral. After September 2019 (post-MGT phase), the same practice offered patients genetic testing in a single clinical encounter with a breast surgeon. We evaluated the waiting time between referral and GC visit in the pre-MGT phase and compared the uptake and positivity rates between both phases. In the pre-MGT phase (204 patients), the median waiting time for GC visit was seven days for patients with a newly diagnosed cancer, 211 days for patients with a personal history of cancer, and 224 days for non-cancer patients who had a family history. A total of 105 (51.5%) patients completed a GC appointment. In the post-MGT phase (202 patients), a significantly higher proportion of patients (88.1%, p < 0.001) consented to genetic testing, while the proportion of patients who tested positive was lower (pathogenic variant: 11.9% vs. 20.0%; variant of uncertain significance: 19.9% vs. 28.0%; p = 0.047). Implementing MGT can reduce the number of clinical visits, significantly shorten patients' wait time to test initiation, and increase the completion of genetic testing. Successful integration of this model relied on the genetic expertise of the breast surgeon involved and the support of the GC team.

Magnetic Seeds: An Alternative to Wire Localization for Nonpalpable Breast Lesions.

INTRODUCTION: Magnetic seeds have emerged as an alternative to wires for localization of nonpalpable breast lesions. The purpose of this study was to evaluate the utility of magnetic seeds compared to wires for preoperative localization. MATERIALS AND METHODS: A retrospective cohort analysis of magnetic seed localization (MSL) and wire localization (WL) excisional biopsies and lumpectomies performed at a single institution was conducted. Indication, age, BMI, number of markers, procedure type, operative time, and postoperative opioid administration were reviewed. Impact of localization method on operative time, specimen volume, postoperative opioid administration, and re-excision rate were assessed. RESULTS: A total of 608 MSL procedures in 601 patients were compared to 628 WL procedures in 620 patients. MSL excisional biopsies were significantly longer (37.0 minutes) than WL excisional biopsies (31.9 minutes, P< .001), but in lumpectomies without axillary surgery, MSL procedures (42.3 minutes) were significantly shorter than WL procedures (46.9 minutes, P = .017). Significantly less tissue was excised during MSL lumpectomies (68.5 cm3) and excisional biopsies (32.3 cm3) than WL lumpectomies (78.1 cm3, P = .039) and excisional biopsies (38.7 cm3, P = .018). Postoperative opioid administration was similar for MSL and WL procedures (P = .076). Re-excision rates for MSL lumpectomies were significantly higher for ductal carcinoma in situ (35.3% MSL vs. 18.5% WL, P = .013), but were similar for invasive carcinoma (14.4% MSL vs. 17.7% WL, P = .290). Logistic regression analysis showed no association between localization method and re-excision (OR 1.007, 95% CI 0.681-1.488; P = .973). CONCLUSION: MSL is a feasible alternative to WL for excision of nonpalpable breast lesions with regard to surgical outcomes.

Familial pancreatic cancer: who should be considered for genetic testing?

BACKGROUND: Determining how many female patients who underwent breast imaging meet the eligibility criteria for genetic testing for familial pancreatic cancer (FPC). METHODS: A total of 42,904 patients seen at the Newton-Wellesley Hospital between 2007 and 2009 were retrospectively reviewed. The first four categories were based on pancreatic cancer-associated syndromes: (1) hereditary breast and ovarian cancer (HBOC), (2) Lynch syndrome (LS), (3) familial atypical multiple mole melanoma (FAMMM), and (4) family history of FPC (FH-FPC). PancPRO (5) and MelaPRO (6) categories were based on risk scores from Mendelian risk prediction tool. RESULTS: Exactly 4445 of 42,904 patients were found to be in at least one of the six risk categories. About 5.7% of patients were classified as being at high risk for HBOC, 2.3% as being at high risk for LS, 0.1% as being at high risk for FAMMM, 0.1% as being at high risk for FH-FPC, 2.7% as being at high risk based on PancPRO, and 0.2% as being at high risk based on MelaPRO. CONCLUSION: About 10.4% of the female patients were classified as being at high risk for FPC. This finding emphasizes the importance of applying criteria to the general population, in order to ensure that individuals with high risk are identified early.

Penetrance of male breast cancer susceptibility genes: a systematic review.

PURPOSE: Several male breast cancer (MBC) susceptibility genes have been identified, but the MBC risk for individuals with a pathogenic variant in each of these genes (i.e., penetrance) remains unclear. We conducted a systematic review of studies reporting the penetrance of MBC susceptibility genes to better summarize current estimates of penetrance. METHODS: A search query was developed to identify MBC-related papers indexed in PubMed/MEDLINE. A validated natural language processing method was applied to identify papers reporting penetrance estimates. These penetrance studies' bibliographies were reviewed to ensure comprehensiveness. We accessed the potential ascertainment bias for each enrolled study. RESULTS: Fifteen penetrance studies were identified from 12,182 abstracts, covering five purported MBC susceptibility genes: ATM, BRCA1, BRCA2, CHEK2, and PALB2. Cohort (n = 6, 40%) and case-control (n = 5, 33%) studies were the two most common study designs, followed by family-based (n = 3, 20%), and a kin-cohort study (n = 1, 7%). Seven of the 15 studies (47%) adjusted for ascertainment adequately and therefore the MBC risks reported by these seven studies can be considered applicable to the general population. Based on these seven studies, we found pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 show an increased risk for MBC. The association between BRCA1 and MBC was not statistically significant. CONCLUSION: This work supports the conclusion that pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 increase the risk of MBC, whereas pathogenic variants in BRCA1 may not be associated with increased MBC risk.

Nipple-Sparing Mastectomy versus Skin-Sparing Mastectomy: Does Saving the Nipple Impact Short- and Long-Term Patient Satisfaction?

BACKGROUND: Nipple-sparing mastectomy (NSM) is an oncologically safe alternative to skin-sparing mastectomy (SSM). This study evaluated whether NSM patients were more satisfied than SSM patients in short- and long-term follow-up. METHODS: Women who underwent NSM or SSM between 2009 and 2019 completed a postoperative BREAST-Q survey at least 1 year after surgery and patient characteristics were compared. Patient satisfaction at 1-5 years and 6-10 years after NSM and SSM were analyzed. RESULTS: Overall, 431 patients were included; 247 had NSM and 184 had SSM 1-10 years prior to BREAST-Q survey completion. SSM patients were older, had higher body mass index (BMI), larger breast weight, and more hypertension than NSM patients, but oncologic treatments were similar between groups. BREAST-Q Psychosocial Well-Being and Sexual Well-Being scores were significantly higher in NSM patients compared with SSM patients in the 1-5 years cohort; however, scores attenuated in the 6-10 years cohort. Satisfaction with breasts was nearly significantly higher in NSM patients compared with SSM patients in the 1-5 years cohort (p = 0.056), but no different in the 6-10 years cohort. Receipt of adjuvant chemotherapy, receipt of postmastectomy radiation therapy, and BMI ≥30 were independent risk factors for dissatisfaction with breasts. CONCLUSIONS: Women who are not candidates for NSM should be reassured that long-term qualify of life is not significantly different between SSM and NSM. Dissatisfaction with reconstructed breasts is linked with other factors (besides the nipple), which patients should be made aware of at the time of surgical decision making.

Disparities in Genetic Testing for Heritable Solid-Tumor Malignancies.

Genetic testing offers providers a potentially life saving tool for identifying and intervening in high-risk individuals. However, disparities in receipt of genetic testing have been consistently demonstrated and undoubtedly have significant implications for the populations not receiving the standard of care. If correctly used, there is the potential for genetic testing to play a role in decreasing health disparities among individuals of different races and ethnicities. However, if genetic testing continues to revolutionize cancer care while being disproportionately distributed, it also has the potential to widen the existing mortality gap between various racial and ethnic populations.

Search Behavior Regarding Cancer Susceptibility Genes Using a Clinical Decision Support Tool for Gene-Specific Penetrance: Content Analysis.

BACKGROUND: Genetic testing for germline cancer susceptibility genes is widely available. The Ask2Me.org (All Syndromes Known to Man Evaluator) tool is a clinical decision support tool that provides evidence-based risk predictions for individuals with pathogenic variants in cancer susceptibility genes. OBJECTIVE: The aim of this study was to understand the search behavior of the Ask2Me.org tool users, identify the patterns of queries entered, and discuss how to further improve the tool. METHODS: We analyzed the Ask2Me.org user-generated queries collected between December 12, 2018, and October 8, 2019. The gene frequencies of the user-generated queries were compared with previously published panel testing data to assess the correspondence between usage and prevalence of pathogenic variants. The frequencies of prior cancer in the user-generated queries were compared with the most recent US population-based cancer incidence. RESULTS: A total of 10,085 search queries were evaluated. The average age submitted in the queries was 48.8 (SD 16.5) years, and 84.1% (8478/10,085) of the submitted queries were for females. BRCA2 (1671/10,085, 16.6%), BRCA1 (1627/10,085, 16.1%), CHEK2 (994/10,085, 9.9%), ATM (662/10,085, 6.6%), and APC (492/10,085, 4.9%) were the top 5 genes searched by users. There was a strong linear correlation between genes queried by users and the frequency of pathogenic variants reported in published panel testing data (r=0.95, r2=0.90, P<.001). Over half of the queries (5343/10,085, 53.0%) included a prior personal history of cancer. The frequencies of prior cancers in the queries on females were strongly correlated with US cancer incidences (r=0.97, r2=0.95, P<.001), while the same correlation was weaker among the queries on males (r=0.69, r2=0.47, P=.02). CONCLUSIONS: The patients entered in the Ask2Me.org tool are a representative cohort of patients with pathogenic variants in cancer susceptibility genes in the United States. While a majority of the queries were on breast cancer susceptibility genes, users also queried susceptibility genes with lower prevalence, which may represent a transformation from single gene testing to multigene panel testing. Owing to these changing tides, more efforts are needed to improve evidence-based clinical decision support tools to better aid clinicians and their practice.

Second invasive breast cancers in patients treated with breast-conserving therapy.

OBJECTIVE: Second breast cancers after breast-conserving therapy (BCT) include ipsilateral breast tumor recurrence (IBTR) and metachronous contralateral breast cancer (CBC). Each IBTR is further classified as true recurrence (TR) or new primary tumor (NP). We aim to compare survival outcomes of TR, NP and CBC, and explore the optimal treatments. METHODS: 168,427 patients with primary breast cancer who underwent BCT between 1990 and 2005 were identified in the SEER database. The risks of IBTR and CBC were estimated by annual hazard rate. The breast cancer-specific survival (BCSS) were assessed using multivariable Cox regression analysis. RESULTS: With median follow-up of 13 years after BCT, 5413 patients developed an IBTR and 4050 patients had a CBC. The risk of IBTR peaked between 10 and 15 years after BCT, while the risk of CBC distributed evenly. 45.9% of IBTRs were classified as a TR and 54.1% as an NP. The time interval from primary breast cancer to NP was longer than to TR and CBC (P < 0.001). Patients with TR had a poorer BCSS than NP (P = 0.003) and CBC (P = 0.002). There was no difference in BCSS between mastectomy and repeat BCT for treating TR (P = 0.584) or NP (P = 0.243). The BCSS of CBCs treated with BCT was better than mastectomy (P = 0.010). Chemotherapy didn't improve the survival of patients with TR (P = 0.058). However, TRs with grade III or negative hormone receptors benefited from chemotherapy significantly. CONCLUSION: Patients with TR had a poorer BCSS than NP and CBC. Classifying IBTR may provide clinical significance for treatments.

Disease Spectrum of Breast Cancer Susceptibility Genes.

BACKGROUND: Pathogenic variants in cancer susceptibility genes can increase the risk of a spectrum of diseases, which clinicians must manage for their patients. We evaluated the disease spectrum of breast cancer susceptibility genes (BCSGs) with the aim of developing a comprehensive resource of gene-disease associations for clinicians. METHODS: Twelve genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RECQL, STK11, and TP53), all of which have been conclusively established as BCSGs by the Clinical Genome Resource (ClinGen) and/or the NCCN guidelines, were investigated. The potential gene-disease associations for these 12 genes were verified and evaluated based on six genetic resources (ClinGen, NCCN, OMIM, Genetics Home Reference, GeneCards, and Gene-NCBI) and an additional literature review using a semiautomated natural language processing (NLP) abstract classification procedure. RESULTS: Forty-two diseases were found to be associated with one or more of the 12 BCSGs for a total of 86 gene-disease associations, of which 90% (78/86) were verified by ClinGen and/or NCCN. Four gene-disease associations could not be verified by either ClinGen or NCCN but were verified by at least three of the other four genetic resources. Four gene-disease associations were verified by the NLP procedure alone. CONCLUSION: This study is unique in that it systematically investigates the reported disease spectrum of BCSGs by surveying multiple genetic resources and the literature with the aim of developing a single consolidated, comprehensive resource for clinicians. This innovative approach provides a general guide for evaluating gene-disease associations for BCSGs, potentially improving the clinical management of at-risk individuals.

The Association Between Cardiac Mortality and Adjuvant Radiation Therapy Among Older Patients With Stage I Estrogen Positive Breast Cancer: A Surveillance, Epidemiology, and End Results (SEER)-Based Study on Cardiac Mortality and Radiation Therapy.

PURPOSE: We evaluated the risk of cardiac mortality in older patients who receive adjuvant radiation therapy (RT) for stage I breast cancer to determine whether this risk persists in the modern era. METHODS AND MATERIALS: Using the 2000 to 2015 Surveillance, Epidemiology, and End Results program data, we performed a population-based cohort study to evaluate the association between adjuvant breast RT, tumor laterality, and cardiac-specific survival (CSS) among patients 60 and older with stage I estrogen receptor positive breast cancer who received breast-conserving surgery and RT. RESULTS: At a median follow-up of 6 years (range, 0-15.9 years), patients receiving RT for left-sided breast cancer demonstrated no difference in 5- and 10-year CSS compared with those with right-sided breast cancer (5 year 98.3% vs 98.2%, 10 year 94.3% vs 93.9%; log-rank P = .56). Cox proportional hazards regression analysis confirmed the lack of association of tumor laterality on adjusted 5-year CSS (hazard ratio [HR] = 0.96; 95% confidence interval [CI] = 0.87-1.06), breast-cancer specific survival (HR = 0.96; 95% CI = 0.85-1.09), and overall survival (HR = 0.98; 95% CI = 0.94-1.03). There was also no association of inner versus outer quadrant location on adjusted 5-year CSS for right-sided (HR = 1.06; 95% CI = 0.89-1.12) and left-sided breast cancer (HR = 0.95; 95% CI = 0.79-1.15). CONCLUSIONS: With modern radiation therapy techniques, older patients who received left-sided RT for stage I estrogen-receptor positive breast cancer do not demonstrate an increased risk of cardiac mortality compared with patients with right-sided breast cancer. RT can be offered to older patients without concern for inducing cardiac-related death.

Management and outcomes of men diagnosed with primary breast cancer.

BACKGROUND: Fewer than 1% of all breast cancers occur in men. As a result, a distinct lack of data exists regarding the management and outcomes in this cohort. METHODS: Any male patient with pathologically confirmed breast cancer diagnosed between August 2000 and October 2017 at either Massachusetts General Hospital or Brigham and Women's Hospital/Dana-Farber Cancer Institute and their affiliate satellite locations were included. Primary chart review was used to assess clinical and pathologic characteristics. Patient and treatment variables were reported via descriptive statistics. Local-regional failure (LRF), overall survival (OS), breast cancer-specific survival (BCSS), and disease-free survival (DFS) were estimated using the Kaplan-Meier method. RESULTS: 100 patients were included in this study. Median follow-up was 112 months (range 1-220 months). Approximately 1/3 of patients experienced at least a 3-month delay to presentation. 83 patients ultimately underwent mastectomy as definitive surgical treatment. 46 patients received adjuvant radiation therapy, and 37 patients received chemotherapy. Of 82 hormone receptor-positive patients with invasive cancer, 94% (n = 77) received endocrine therapy. Of the fifty-eight patients who underwent genetic testing, 15 (26%) tested positive. The 5-year OS, BCSS, DFS, and LRF rates were 91.5%, 96.2%, 86%, and 4.8%, respectively. Delay to presentation was not associated with worse survival. CONCLUSIONS: Male breast cancer remains a rare diagnosis. Despite this, the majority of patients in this study received standard of care therapy and experienced excellent oncologic outcomes. Penetration for genetic testing improved over time.

Disease spectrum of gastric cancer susceptibility genes.

Pathogenic variants in germline cancer susceptibility genes can increase the risk of a large number of diseases. Our study aims to assess the disease spectrum of gastric cancer susceptibility genes and to develop a comprehensive resource of gene-disease associations for clinicians. Twenty-seven potential germline gastric cancer susceptibility genes were identified from three review articles and from six commonly used genetic information resources. The diseases associated with each gene were evaluated via a semi-structured review of six genetic resources and an additional literature review using a natural language processing (NLP)-based procedure. Out of 27 candidate genes, 13 were identified as gastric cancer susceptibility genes (APC, ATM, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH-Biallelic, PALB2, SMAD4, and STK11). A total of 145 gene-disease associations (with 45 unique diseases) were found to be associated with these 13 genes. Other gastrointestinal cancers were prominent among identified associations, with 11 of 13 gastric cancer susceptibility genes also associated with colorectal cancer, eight genes associated with pancreatic cancer, and seven genes associated with small intestine cancer. Gastric cancer susceptibility genes are frequently associated with other diseases as well as gastric cancer, with potential implications for how carriers of these genes are screened and managed. Unfortunately, commonly used genetic resources provide heterogeneous information with regard to these genes and their associated diseases, highlighting the importance of developing guides for clinicians that integrate data across available resources and the medical literature.

Non-medullary Thyroid Cancer Susceptibility Genes: Evidence and Disease Spectrum.

BACKGROUND: The prevalence of non-medullary thyroid cancer (NMTC) is increasing worldwide. Although most NMTCs grow slowly, conventional therapies are less effective in advanced tumors. Approximately 5-15% of NMTCs have a significant germline genetic component. Awareness of the NMTC susceptibility genes may lead to earlier diagnosis and better cancer prevention. OBJECTIVE: The aim of this study was to provide the current panorama of susceptibility genes associated with NMTC and the spectrum of diseases associated with these genes. METHODS: Twenty-five candidate genes were identified by searching for relevant studies in PubMed. Each candidate gene was carefully checked using six authoritative genetic resources: ClinGen, National Comprehensive Cancer Network guidelines, Online Mendelian Inheritance in Man, Genetics Home Reference, GeneCards, and Gene-NCBI, and a validated natural language processing (NLP)-based literature review protocol was used to further assess gene-disease associations where there was ambiguity. RESULTS: Among 25 candidate genes, 10 (APC, DICER1, FOXE1, HABP2, NKX2-1, PRKAR1A, PTEN, SDHB, SDHD, and SRGAP1) were verified among the six genetic resources. Two additional genes, CHEK2 and SEC23B, were verified using the NLP protocol. Seventy-nine diseases were found to be associated with these 12 NMTC susceptibility genes. The following diseases were associated with more than one NMTC susceptibility gene: colorectal cancer, breast cancer, gastric cancer, kidney cancer, gastrointestinal stromal tumor, paraganglioma, pheochromocytoma, and benign skin conditions. CONCLUSION: Twelve genes predisposing to NMTC and their associated disease spectra were identified and verified. Clinicians should be aware that patients with certain pathogenic variants may require more aggressive surveillance beyond their thyroid cancer risk.