Breast Cancer Research and Treatment

Factors associated with endometrial pathology during tamoxifen therapy in women with breast cancer: a retrospective analysis of 821 biopsies

This study evaluated the factors associated with endometrial pathologies during tamoxifen use in women with breast cancer. This study analyzed 821 endometrial biopsies from women who received tamoxifen for breast cancer. Clinical characteristics were compared according to the presence of endometrial pathology (atypical hyperplasia and cancer). In addition, patients with endometrial polyps were compared with women with normal histology. Among 821 biopsies, atypical endometrial hyperplasia and cancer were diagnosed in 7 women each. Endometrial polyps were found in 173 women, and 634 women presented normal histology. In comparing women with endometrial pathology (atypical hyperplasia and cancer, n = 14) and those without pathology, parity was significantly lower (P = 0.014) and endometrial thickness was significantly higher (P < 0.001) in women with pathology. In addition, abnormal uterine bleeding was more common in the pathology group (P < 0.001). However, age, body mass index, menopausal status, intrauterine device use, history of diabetes mellitus, and duration of tamoxifen use did not differ according to the presence of pathology. In comparing women with endometrial polyps and those with normal endometrium, significant differences were found in parity (P < 0.001), duration of tamoxifen use (P = 0.003), and endometrial thickness (P < 0.001), but not in the presence of abnormal vaginal bleeding. Parity, endometrial thickness, and the presence of abnormal vaginal bleeding, but not age, body mass index, and menopausal status, may be associated with endometrial pathology during tamoxifen use in women with breast cancer. This finding might provide useful information for gynecological surveillance and counseling during tamoxifen treatment.

Time trends, uptake, and oncological effects of risk-reducing surgeries in 3067 Danish BRCA1/2 carriers: a population-based study with matched controls

Abstract Purpose Knowledge of the uptake and breast and ovarian cancer-preventive and survival effects of bilateral risk-reducing mastectomy (BRRM) and salpingo-oophorectomy (RR-BSO) in female BRCA1/2 carriers is essential for optimized decision-making. This study aimed to examine time trends in the number of registered unaffected BRCA1/2 carriers, BRRM and RR-BSO uptake, and oncological effects of risk-reducing surgeries in a nationwide Danish cohort with matched controls. Methods We included 3067 female BRCA1/2 carriers registered in the Hereditary Breast and Ovarian Cancer Registry and 30,652 age-matched controls between 2000 and 2022. Data were retrieved from national health registries. Uptake and oncological effects of risk-reducing surgeries were assessed using cumulative incidences and Cox proportional hazards models with 95% confidence intervals (CI). Results Annual numbers of registered unaffected BRCA1/2 carriers, BRRM, and RR-BSO increased over time. BRRM and RR-BSO uptake 10 years after genetic test varied with the age at genetic test and parity. BRRM reduced the hazard rate of breast cancer by 94% [hazard ratio (HR) 0.06, CI 0.01–0.25]. The same pattern was not found for RR-BSO (HR = 1.31, CI 0.90–1.91). Compared to controls, BRCA1/2 carriers had an increased hazard rate for breast cancer before BRRM (HR 7.49, CI 5.81–9.42). Conclusion BRRM’s large protective effect against breast cancer in BRCA1/2 carriers was confirmed, in contrast to that of RR-BSO. There were tendencies toward a reduction in overall mortality rates after BRRM, and compared with controls, we saw tendencies toward higher mortality rates before BRRM.

Effectiveness of gonadotropin-releasing hormone agonists for ovarian function suppression in premenopausal patients with hormone receptor-positive breast cancer: a retrospective single-center real-world study

Abstract Purpose This study evaluated the effectiveness of ovarian function suppression (OFS) of various gonadotropin-releasing hormone agonists (GnRHa) combined with aromatase inhibitors (AI) in premenopausal patients with hormone receptor-positive (HR-positive) breast cancer. Potential risk factors associated with insufficient OFS were analyzed. Patients and methods Premenopausal HR-positive breast cancer patients who had received AI with GnRHa were studied retrospectively. Patients were divided into different groups according to monthly or trimonthly GnRHa schedules they received, and the effectiveness of OFS was compared between groups. Insufficient OFS was defined as at least one instance of estradiol ≥ 30 pg/ml. Patient data was gathered from medical records for this comparison. Results Of the 264 patients enrolled in this study, 117 were administered 3.6 mg of goserelin monthly (goserelin 1 M group), 63 received 3.75 mg of leuprorelin monthly (leuprorelin 1 M group) and 84 were given 11.25 mg of leuprorelin every three months (leuprorelin 3 M group). Overall, 7.20% experienced insufficient OFS. The incidence rates in the three GnRHa depot groups were 7.69%, 6.35%, and 7.14%, respectively, without a significant statistical difference (P = 0.900). Notably, younger patients exhibited a higher likelihood of insufficient OFS [OR = 0.900, 95%CI (0.824–0.982), P = 0.018]. Conclusion Insufficient OFS remains a concern during GnRHa and AI treatment. The effectiveness of the three GnRHa depots commonly used in China seems comparable. Younger patients face a heightened risk of insufficient OFS.

Hereditary cancer testing in a diverse sample across three breast imaging centers

Abstract Purpose Up to 10% of all breast cancers (BC) are attributed to inherited pathogenic variants (PV) in BC susceptibility genes; however, most carriers of PVs remain unidentified. Here, we sought to determine the yield of hereditary cancer gene PVs among diverse women attending breast imaging centers, who could benefit from enhanced surveillance and/or risk reduction interventions. Methods This cross-sectional retrospective cohort study included consecutive women, unselected for personal or family cancer history, who were offered genetic testing for hereditary cancer genes at the time of breast imaging at three centers (November 2020–March 2022). Results Among 1943 patients (median age: 66 years), self-reported race/ethnicity was White (34.5%), Hispanic (27.7%), African American (17.9%), Asian (4.5%), Ashkenazi Jewish (0.6%), Other (3.5%), and missing (13.0%). Thirty-nine patients (2%) were identified as carriers of a PV in an autosomal dominant clinically actionable hereditary breast and ovarian cancer (HBOC)-related or Lynch syndrome gene, most frequently, BRCA2 (6/39; 15.4%), PALB2 (8/39; 20.5%), CHEK2 (10/39; 25.6%), and PMS2 (5/39; 12.8%). Of the 34 PVs with known race/ethnicity, 47% were detected among non-White patients. Overall, 354/1,943 (18.2%) of patients met NCCN guidelines for HBOC gene testing and only 15/39 (38.5%) patients with an autosomal dominant clinically actionable PV met guidelines. Conclusion This population health approach extended the reach of genetic cancer risk assessment in a diverse population and highlighted the limits of a guideline-based approach. This may help address inequity in access to risk-appropriate screening and cancer prevention.

Ovarian function recovery in breast cancer patients receiving adjuvant anastrozole treatment: updated results from the phase 3 DATA trial

Abstract Purpose Patients with chemotherapy-induced ovarian function failure (CIOFF) may experience ovarian function recovery (OFR). Earlier, we showed that OFR during treatment with anastrozole impacted the prognosis of hormone receptor-positive (HR+) breast cancer (BC) patients with CIOFF. Here, we present the long-term follow-up results. Methods Postmenopausal women with HR+ BC who were 45–57 years of age and received chemotherapy were identified from the phase 3 DATA study (NCT00301457) on the extended use of anastrozole. Eligible patients were categorised into two groups: patients with CIOFF and definitely postmenopausal patients. Patients with CIOFF were monitored for OFR. Disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS) were compared between patients with OFR and patients without OFR using multivariable Cox regression analyses, including OFR as a time-dependent covariate. BC-specific mortality (BCSM) was compared between groups using the Fine and Gray method. Results This study included 656 patients: 395 patients with CIOFF and 261 definitely postmenopausal patients. OFR occurred in 39 (12%) of 329 patients with CIOFF who were monitored for OFR. The median follow-up time was 13.3 years. Patients with OFR experienced a deterioration in DFS (hazard ratio (HR) = 1.54; 95% confidence interval (CI) 0.85–2.81), DRFS (HR = 1.51; 95% CI 0.73–3.11), OS (HR = 1.64; 95% CI 0.75–3.55), and BCSM (subdistribution HR = 1.98; 95% CI 0.84–4.63) when compared with patients without OFR. Conclusion In patients with CIOFF, OFR during treatment with anastrozole was associated with a deterioration in BC outcomes. These findings underscore the importance of adequate ovarian function suppression in this subgroup of patients.

The impact of cardiovascular risk factors on cancer progression: a prospective study in female breast cancer survivors

Predicting the likelihood of carrying BRCA1 or BRCA2 pathogenic variants in high-risk Pakistani breast cancer patients

Second primary non-breast cancers in young breast cancer survivors

Development of a novel prediction model for carriage of BRCA1/2 pathogenic variant in Japanese patients with breast cancer based on Japanese organization of hereditary breast and ovarian cancer registry data

With the increasing demand for BRCA genetic testing, most existing prediction models were developed using data from individuals of European descent. This study aimed to identify clinicopathological factors of hereditary breast and ovarian cancer (HBOC) syndrome and develop the first Japanese-specific prediction model for BRCA pathogenic variant carriers in Japan. We utilized data from 3072 Japanese patients with breast cancer aggregated by the Japanese Organization of Hereditary Breast and Ovarian Cancer registry. Prediction models were developed using 70% of the overall dataset and validated using the remaining 30%. Factors associated with the BRCA pathogenic variant status were identified using logistic univariate analysis, and significant factors were further analyzed using logistic multivariate analysis to develop prediction models for BRCA1/2 (BRCA1 and/or BRCA2), BRCA1, and BRCA2 pathogenic variants. BRCA1 showed associations with aggressive clinicopathological factors such as triple-negative breast cancer and nuclear grade 3. Moreover, the prediction model showed a high area under the curve (AUC) of 0.879. By contrast, BRCA2 exhibited fewer characteristic associated factors, and the AUC of the model was 0.669. Common factors shared by BRCA1/2, BRCA1, and BRCA2 were the age at diagnosis of breast cancer and the youngest age of relatives with breast cancer. Consistent with previous research, early-onset breast cancer appeared to be strongly associated with HBOC. We successfully developed prediction models for BRCA1/2, BRCA1, and BRCA2 pathogenic variants. By accurately stratifying patients' risk and guiding targeted screening and preventative interventions, these models will contribute to improved management and outcomes of HBOC.

BRCA testing utilization among commercially insured women with breast or ovarian cancer

This report examines utilization of germline BRCA genetic testing among women with breast or ovarian cancer in the context of current clinical guidelines for testing. Linked IQVIA commercial claims and electronic medical record data were used to analyze BRCA test utilization among women aged 18-64 years with newly diagnosed breast cancer or ovarian cancer during 2016-2021, excluding 2018. Log-binomial regression models were used to estimate prevalence ratios (PRs) comparing utilization of testing by cancer type, age group, race, and year. Among commercially insured women with newly diagnosed breast cancer (n = 19,139) or epithelial ovarian cancer (n = 1639), 50 and 47%, respectively, received germline BRCA testing during the study years. BRCA testing rates were higher among women with breast cancer aged 18-50 years (69%) compared to those aged 51-64 years (39%). Overall utilization among women with breast or ovarian cancer was slightly lower in 2021 compared to 2019 and 2020. Compared with White women with breast cancer, Asian women were less likely (PR, 0.83 [95% CI, 0.74-0.92]) to receive testing. Nearly one-third of women who had breast cancer at age 50 or younger and a majority of women with ovarian cancer had no germline BRCA testing recorded within 1 year of diagnosis. Under current (2024) guidelines, these women and their family members are eligible for genetic counseling and testing to guide preventive interventions for future cancers. Healthcare providers have an important role in offering genetic services to women and their families, ensuring that eligible women receive recommended care.

Considerations for hereditary breast and ovarian cancer syndrome molecular diagnosis: experience from the clinical practice

The implementation of the next-generation sequencing (NGS) in clinical practice has improved the genetic diagnosis of Hereditary Breast and Ovarian Cancer Syndrome (HBOC). We aimed to evaluate the diagnostic outcomes of using an NGS cancer gene panel in clinical practice for patients selected based on personal and/or family history of breast, ovarian, prostate, melanoma, and other HBOC-associated cancers. The study series included 2561 consecutive Spanish individuals referred for genetic testing, comprising 2445 cancer patients and 116 healthy individuals with family history of HBOC. Eleven HBOC susceptibility genes (BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51C, RAD51D, TP53, and PTEN) and three Lynch Syndrome genes (MLH1, MSH2, and MSH6) available for opportunistic testing were analyzed using a commercial Hereditary Cancer Panel and an in-house bioinformatics pipeline. Overall, the diagnostic yield was 11.0% in cancer patients and 8.6% in healthy individuals with a family history of breast/ovarian cancer. Pathogenic variants in high-risk genes were more frequent in patients with multiple HBOC tumors and a family history of different HBOC cancers. Additionally, we diagnosed five families with Lynch syndrome through opportunistic testing. Testing cancer susceptibility genes using an agnostic strategy confers a diagnostic benefit for hereditary cancer syndromes compared to phenotype-driven test, without adding complexity to the study. The analysis of healthy individuals with a family history of HBOC detects pathogenic variants in a cost-efficient percentage of cases, resulting in a good alternative strategy when the index case is unavailable.

Contribution of large genomic rearrangements in BRCA1/2 genes and CHEK2 1100delC allele variant to the development of breast/ovarian cancer in Argentinian population

Among women in Argentina, the most common cancer is breast cancer (BC) with 21,631 new cases and 6436 deaths per year. The ovarian cancer (OC) is fifteenth in frequency. The contribution of cancer-related large genomic rearrangements (LGRs) of the BRCA1/BRCA2 genes and the 1100delC allelic variant in the CHEK2 gene has not yet been widely studied in our population. LGRs in the BRCA1/BRCA2 genes and the CHEK2 1100delC variant were analyzed using the MLPA technique in 85 unselected Argentinian BC/OC patients. A pathogenic genetic variant (PV) was found in eleven out of 85 (12,9%) patients, 10 were LGRs in the BRCA1 gene, 9 deletions and one duplication and one the CHEK2 1100delC. Large deletions of exons 1-2 and 15 in BRCA1 gene were recurrent anomalies in our series. LGRs in the BRCA1 gene contributed significantly to the burden of PVs responsible for the development of BC and OC in our study population. On the other hand, the 1100delC variant in CHEK2 was observed at a very low frequency in our series formed mainly by the Spanish, Italian and Amerindian ethnic groups.

Northern origin of the BRCA2 c.5286 T &gt; G founder allele

Ethnicity-specific BRCA1, BRCA2, PALB2, and ATM pathogenic alleles in breast and ovarian cancer patients from the North Caucasus

Mountain areas of the North Caucasus host several large ethnic communities that have preserved their national identity over the centuries. This study involved high-grade serous ovarian cancer (HGSOC) and breast cancer (BC) patients from Dagestan (HGSOC: 37; BC: 198), Kabardino-Balkaria (HGSOC: 68; BC: 155), North Ossetia (HGSOC: 51; BC: 104), Chechnya (HGSOC: 68; BC: 79), Ingushetia (HGSOC: 19; BC: 103), Karachay-Cherkessia (HGSOC: 13; BC: 47), and several Armenian settlements (HGSOC: 16; BC: 101). The group of BC patients was enriched by young-onset and/or family history-positive and/or bilateral and/or receptor triple-negative cases. The entire coding region of BRCA1, BRCA2, PALB2, and ATM genes was analyzed by next-generation sequencing. A significant contribution of BRCA1/2 pathogenic variants (PVs) to HGSOC and BC development was observed across all North Caucasus regions (HGSOC: 19-39%; BC: 6-13%). Founder alleles were identified in all ethnic groups studied, e.g., BRCA1 c.3629_3630delAG in Chechens, BRCA2 c.6341delC in North Ossetians, BRCA2 c.5351dupA in Ingush, and BRCA1 c.2907_2910delTAAA in Karachays. Some BRCA1/2 alleles, particularly BRCA2 c.9895C > T, were shared by several nationalities. ATM PVs were detected in 14 patients, with c.1673delG and c.8876_8879delACTG alleles occurring twice each. PALB2 heterozygosity was observed in 5 subjects, with one variant seen in 2 unrelated women. This study adds to the evidence for the global-wide contribution of BRCA1/2 genes to HGSOC and BC morbidity, although the spectrum of their PVs is a subject of ethnicity-specific variations. The data on founder BRCA1/2 alleles may be considered when adjusting the BRCA1/2 testing procedure to the ethnic origin of patients.

The RAD51D c.82G&gt;A (p.Val28Met) variant disrupts normal splicing and is associated with hereditary ovarian cancer

Mutations in RAD51D are associated with a predisposition to primary ovarian, fallopian tube, and peritoneal carcinoma. Our study aims to characterize a RAD51D missense variant in a hereditary ovarian cancer family. The effects of the RAD51D c.82G>A (p.Val28Met) variant on mRNA splicing were evaluated and characterized using RT-PCR, cloning and DNA sequencing. This variant completely disrupts normal splicing and results in the loss of 3'end of 5'UTR and the entire exon 1 (c.-86_c.82), which presumably leads to loss of the RAD51D protein. The RAD51D c.82G>A (p.Val28Met) variant is clinically significant and classified as likely pathogenic. Our results indicate that the RAD51D c.82G>A (p.Val28Met) variant contributes to cancer predisposition through disruption of normal mRNA splicing. The identification of this variant in an individual affected with high-grade serous fallopian tube cancer suggests that the RAD51D variant may contribute to predisposition to the ovarian cancer in this family.

A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia

Pathogenic variants (PVs) in BRCA1 and BRCA2 genes are essential biomarkers of an increased breast and ovarian cancer risk and tumor sensitivity to poly ADP ribose polymerase inhibitors. In Russia, eight PVs were thought to be the most common, among which BRCA1 c.5266dup is the most frequently identified one. We show the distribution of BRCA1/2 PVs identified with quantitative PCR and targeted next-generation sequencing in 1399 ovarian cancer patients recruited into the study from 72 Russian regions in 2015-2021. The most abundant PVs were c.5266dup (41.0%), c.4035del (7.0%), c.1961del (6.3%), c.181 T > G (5.2%), c.3756_3759del (1.8%), c.3700_3704del (1.5%), and c.68_69del (1.5%), all found in BRCA1 and known to be recurrent in Russia. Several other frequent PVs were identified: c.5152 + 1G > T (1.2%), c.1687C > T (1.0%), c.4689C > G (0.9%), c.1510del (0.6%), c.2285_2286del (0.6%) in the BRCA1 gene; and c.5286 T > G (1.2%), c.2808_2811del (0.8%), c.3847_3848del (0.8%), c.658_659del (0.7%), c.7879A > T (0.6%), in the BRCA2 gene. For the most common PV in the BRCA2 gene c.5286 T > G, we suggested that it arose about 700 years ago and is a new founder mutation. This study extends our knowledge about the BRCA1 and BRCA2 pathogenic variants variability.

Mutational spectrum of BRCA1/2 genes in Moroccan patients with hereditary breast and/or ovarian cancer, and review of BRCA mutations in the MENA region

Breast cancer (BC) is the most common form of female cancer around the world. BC is mostly sporadic, and rarely hereditary. These hereditary forms are mostly BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome. BRCA1 and BRCA2 genes are large and had some recurrent mutations specific to some populations. Through this work we analyze the most recurrent mutations in Moroccan population and compared them to a large review of other BRCA1/2 spectrum mutations in the MENA region. We report in this work a series of 163 unrelated patients (the largest series of Moroccan patients) with familial breast and/or ovarian cancer, selected among patients referred to our oncogenetic outpatient clinic, from 2006 to 2021. To identify genetic variants in these two genes, different genetic analysis strategies have been carried out, using Sanger Sequencing DNA or Target Panel Sequencing. Pathogenic variants were identified in 27.6% of patients. The most frequent mutation identified in our patients was the c.1310_1313delAAGA, BRCA2 (33%), and three other mutations seem more frequent in the Moroccan population (33%) of all reported patients: c.798_799delTT, BRCA1; and c.3279delC, BRCA1; and c.7234_7235insG in BRCA2 gene. Through this work, we emphasize the importance of screening for BRCA1 and BRCA2 recurrent mutations in Moroccan patients. Other MENA (MENA: English-language acronym referring to the Middle East and North Africa region) countries had also some recurrent BRCA mutations, which will allow a fast and unexpensive first line genetic analysis and a precise molecular diagnosis. This will allow an adapted follow-up of the patients and a pre-symptomatic diagnosis of their relatives.

Risk of second non-breast primary cancer in Chinese breast cancer patients with germline BRCA1/2 pathogenic variants

Spectrum of germline pathogenic variants in Brazilian hereditary breast/ovarian cancer cases

To define the spectrum of germline pathogenic variants (PVs) and copy number variant (CNV) in cancer susceptibility genes to the burden of breast and ovarian cancer (BC, OvC) in high-risk Brazilians in Minas Gerais with health insurance, southeast Brazil, undergoing multigene panel testing (MGPT). Genotyping eligible individuals with health insurance in the Brazilian healthcare system for Hereditary Breast and Ovarian Cancer Syndrome to undergo molecular testing for 44 or 141-gene panels, a decision that was insurance driven. Overall, 701 individuals clinically defined as high BC/OvC risk, underwent MGPT from 1/2021 to 10/2022, with ~ 50% genotyped with a 44-gene panel and the rest with a 141-gene panel. Overall, 16.4% and 22.6% of genotyped individuals harbored PVs using 44-gene and the 141 gene panel, respectively. The most frequently mutated genes were: BRCA2 (3.7%); BRCA1 (3.6%) and monoallelic MUTYH (3.1%). The rate of PVs detected in high-risk individuals in this study was twice the 10% threshold used in Brazilian health guidelines. MGPT doubled the detection rate of PVs in cancer susceptibility genes in high-risk individuals compared with BRCA1/BRCA2 genotyping alone. The spectrum of PVs in Southern Brazil is diverse, with few recurring variants such as TP53 (0.6%), suggesting regional founder effects. The use of MGPT in hereditary cancer in Minas Gerais significantly increased the detection rate of P/LPVs compared to existing guidelines and should be considered as the primary genotyping modality in assessing hereditary cancer risk in Brazil.

Uptake of screening and risk-reducing recommendations among women with hereditary breast and ovarian cancer syndrome due to pathogenic BRCA1/2 variants evaluated at a large urban comprehensive cancer center

Carriers of pathogenic variants in BRCA1/2 have an elevated lifetime cancer risk warranting high-risk screening and risk-reducing procedures for early detection and prevention. We report on prevention practices among women with pathogenic BRCA variants in order to document follow through with NCCN recommendations and to identify barriers to guideline-recommended care. Our cohort included women who had genetic testing through a cancer genetic clinic and completed a 54-item questionnaire to measure socio-demographics, medical history, rates of cancer screening and risk-reducing surgery, disclosure of test results, and cancer worry. Outcomes included rates of completion of risk-reducing salpingo-oophorectomy (RRSO), risk-reducing mastectomy (RRM), and NCCN risk-reducing and age-dependent screening guidelines (version 3.2019). Multivariable logistic regression analyses were used to evaluate potential predictors of these outcomes. Of 129 evaluable women with pathogenic BRCA1/2 variants, 95 (74%) underwent RRSO and 77 (60%) had RRM, respectively, and 107 (83%) were considered adherent to NCCN guidelines. Women with a history of breast or ovarian cancer were more likely to have RRM (OR = 4.38; 95% CI 1.80-11.51; p = 0.002). Increasing age was associated with an increased likelihood of RRSO (OR = 1.05; 95% CI 1.01-1.09; p = 0.019) and decreased likelihood for RRM (OR = 0.95; 95% CI 0.92-0.99; p = 0.013). Women who had RRM were 3 times more likely to undergo RRSO (OR = 2.81; 95% CI 1.10-7.44; p = 0.025). Women who had genetic testing after June 2013 were less likely to have RRM than those tested before June 2013 (OR = 0.42; 95% CI 0.18-0.95; p = 0.040. None of the other measured factors were associated with rates of RRSO, RRM or follow through with NCCN recommendations. There was near universal (127/129) reported disclosure of genetic test results to family members, resulting in the discovery of a median of 1 relative with a pathogenic variant (range = 0-8). An evaluation of follow up practice in a cohort of women with pathogenic variants in BRCA1/2 revealed high rates of reported completion of screening and surgical risk-reducing recommendations. Educational efforts should continue to reinforce the importance of follow-through with guideline recommended care among this high-risk group.

Uterine cancer in breast cancer survivors: a systematic review

Epidemiological evidence on the risk factors for uterine/endometrial cancer in breast cancer (BCa) survivors is limited and inconsistent. Therefore, we critically reviewed and summarized available evidence related to the risk factors for uterine/endometrial cancer in BCa survivors. We conducted a literature search through PubMed, Web of Science Core Collection/Cited Reference Search, as well as through manual searches of the bibliographies of the articles identified in electronic searches. We included in this review studies that were published up to November 30, 2018 that were accessible in full-text format and were published in English. Of the 27 eligible studies, 96% had > 700 participants, 74% were prospective cohorts, 70% originated outside of the US, 44% reported as having pre-/postmenopausal women, and 26% reported having racially heterogeneous populations. Risk factors positively associated with uterine/endometrial cancer risk among BCa survivors included age at BCa diagnosis > 50 years, African American race, greater BMI/weight gain, and Tamoxifen treatment. For other lifestyle, reproductive and clinical factors, associations were either not significant (parity) or inconsistent (HRT use, menopausal status, smoking status) or had limited evidence (alcohol intake, family history of cancer, age at first birth, oral contraceptive use, age at menopause, comorbidities). We identified several methodological concerns and limitations across epidemiological studies on potential risk factors for uterine/endometrial cancer in BCa survivors, including lack of details on uterine/endometrial cancer case ascertainment, varying and imprecise definitions of important covariates, insufficient adjustment for potential confounders, and small numbers of uterine/endometrial cancer cases in the overall as well as stratified analyses. Based on the available evidence, older age and higher body weight measures appear to be a shared risk factor for uterine/endometrial cancer in the general population as well as in BCa survivors. In addition, there is suggestive evidence that African American BCa survivors have a higher risk of uterine/endometrial cancer as compared to their White counterparts. There is also evidence that Tamoxifen contributes to uterine/endometrial cancer in BCa survivors. Given limitations of existing studies, more thorough investigation of these associations is warranted to identify additional preventive strategies needed for BCa survivors to reduce uterine/endometrial cancer risk and improve overall survival.

Identifying miRNA biomarkers for breast cancer and ovarian cancer: a text mining perspective

microRNA (miRNAs) are small, non-coding RNAs that mediate post-transcriptional gene silencing. Numerous studies have demonstrated the critical role of miRNAs in the development of breast cancer and ovarian cancer. To reduce potential bias from individual studies, a more comprehensive approach of exploring miRNAs in cancer research is essential. This study aims to explore the role of miRNAs in the development of breast cancer and ovarian cancer. Abstracts of the publications were tokenized and the biomedical terms (miRNA, gene, disease, species) were identified and extracted for vectorization. Predictive analyses were conducted with four machine learning models: K-Nearest Neighbors (KNN), Support Vector Machines (SVM), Random Forest (RF), and Naïve Bayes. Both holdout validation and cross-validation were utilized. Feature importance will be identified for miRNA-cancer networks construction. We found that miR-182 is highly specific to female cancers. miR-182 targets different genes in regulating breast cancer and ovarian cancer. Naïve Bayes provided a promising prediction model for breast cancer and ovarian cancer with miRNAs and genes combination, with an accuracy score greater than 60%. Feature importance identified miR-155 and miR-199 are critical for breast cancer and ovarian cancer prediction, with miR-155 being highly related to breast cancer, whereas miR-199 being more associated with ovarian cancer. Our approach effectively identified potential miRNA biomarkers associated with breast cancer and ovarian cancer, providing a solid foundation for generating novel research hypotheses and guiding future experimental studies.

Pathogenic variants among females with breast cancer and a non-breast cancer reveal opportunities for cancer interception

Abstract Purpose Herein, we report the frequency and distribution of germline pathogenic variants (PVs) among females with breast cancer (BC) and at least one other non-BC who underwent multi-gene panel testing (MGPT). Among females with PVs diagnosed first with BC or ovarian cancer (OC), we sought to enumerate the frequency of subsequent PV-associated cancers. Methods Females with BC and cancer of ≥ 1 other site (multiple primary cancers, MPC) who underwent MGPT through Ambry Genetics from March 2012 to December 2016 were included if they had testing of at least 21 genes of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53). Phenotypic data were abstracted from test requisition forms and clinical notes. Results Of 6,617 evaluable patients, most were White (70.8%) and median age at first cancer, second cancer, and MGPT was 49 (interquartile range [IQR]: 18), 59 (IQR: 16), and 63 (IQR: 16) years, respectively. PVs were found among 14.1% (932/6617) of the overall cohort and in 16.4% (440/2687) of females who were diagnosed first with BC. Among those, 55.2% (243/440) had an actionable PV associated with a subsequent cancer diagnosis including 150 OCs. Of the 2443 females with breast and ovarian cancer, few (n = 97, 9.5%) were diagnosed first with OC, limiting our analysis. Conclusions Females with MPC, including BC, have a high frequency of germline PVs (14.1%). These data delineate the opportunities for intercepting subsequent cancers associated with genetic risk among females diagnosed first with BC.

Alterations in the expression of homologous recombination repair (HRR) genes in breast cancer tissues considering germline BRCA1/2 mutation status

Abstract Introduction Homologous recombination (HR) is a crucial DNA-repair mechanism, and its disruption can lead to the accumulation of mutations that initiate and promote cancer formation. The key HR genes, BRCA1 and BRCA2 , are particularly significant as their germline pathogenic variants are associated with a hereditary predisposition to breast and/or ovarian cancer. Materials and methods The study was performed on 45 FFPE breast cancer tissues obtained from 24 and 21 patients, with and without the germline BRCA1/2 mutation, respectively. The expression of 11 genes: BRCA1, BRCA2, ATM, BARD1, FANCA, FANCB, FANCI, RAD50, RAD51D, BRIP1, and CHEK2 was assessed using Custom RT2 PCR Array (Qiagen), and results were analysed using R. Results Cancer tissues from patients with BRCA1 or BRCA2 germline mutations displayed no significant differences in the expression of the selected HR genes compared to BRCA1 or BRCA2 wild-type cancer tissues. In BRCA1 mut cancer tissues, BRCA1 expression was significantly higher than in BRCA2 mut and BRCA wild-type cancer tissues. Conclusions In cancer tissues harbouring either BRCA1 or BRCA2 germline mutations, no significant differences in expression were observed at the mRNA level of any tested HR genes, except BRCA1 . However, the significant differences observed in BRCA1 expression between germline BRCA1 mut , germline BRCA2 mut and BRCA1/2 wt  tissues may indicate a compensatory mechanism at the mRNA level to mitigate the loss of BRCA1 function in the cells.

Carboplatin, gemcitabine, and mifepristone for advanced breast and recurrent/persistent epithelial ovarian cancer

Abstract Purpose Preclinical models of glucocorticoid receptor (GR)-positive breast cancer (BC) and ovarian cancer (OC) suggest GR activity inhibits chemotherapy-induced apoptosis, and GR antagonism using mifepristone (Mif) enhances cytotoxicity. We performed a phase I trial combining mifepristone, carboplatin (C), gemcitabine (G). Methods A standard “3 + 3” dose escalation scheme was used. Objectives were safety and to determine the maximum tolerated dose (MTD) of Mif + CG. CG was administered intravenously on days 1 and 8 of a 21-day cycle, and mifepristone was administered orally the day before and day of chemotherapy. Results Thirty-one patients enrolled with a median age of 54 years; the median prior metastatic regimens were one. Twenty-five patients were evaluable for dose-limiting toxicities (DLT) including 16 BC and 9 OC. Dose was de-escalated to dose level (DL) -1 due to 2/4 neutropenia-related DLT's. DLT definition was updated to exclude hematologic DLTs starting at DL-1. The dose  was further de-escalated due to neutropenia, and 2/3, 1/4 and 0/6 patients experienced a DLT at DL-1, DL-2, and DL-3, respectively. At DL-1, prophylactic pegylated granulocyte colony-stimulating factor (G-CSF) was instituted. Dose levels -1 and -2 were expanded to add 3 and 6 patients, respectively, to evaluate tolerability  in dose levels -1a and -2a. There were 3 major responses (1CR, 2PR) at DL1, and 1 CR at DL-1. No responses were observed at lower levels. Conclusion The MTD was carboplatin AUC 2  + gemcitabine 600 mg/m2 on D1 and 8 with Mif 300 mg D-1 and D1 with pegylated G-CSF administered on day 9 of a 21-day cycle.

BRCA1 and BRCA2 germline mutation analysis from a cohort of 1267 patients at high risk for breast cancer in Brazil

We determined the frequency and mutational spectrum of BRCA1 and BRCA2 in a series of patients at high risk for developing breast cancer from Brazil. A total of 1267 patients were referred for BRCA genetic testing, and no obligation of fulfilling criteria of mutation probability methods for molecular screening was applied. Germline deleterious mutations in BRCA1/2 (i.e., pathogenic/likely pathogenic variants) were identified in 156 out of 1267 patients (12%). We confirm recurrent mutations in BRCA1/2, but we also report three novel mutations in BRCA2, not previously reported in any public databases or other studies. Variants of unknown significance (VUS) represent only 2% in this dataset and most of them were detected in BRCA2. The overall mutation prevalence in BRCA1/2 was higher in patients diagnosed with cancer at age > 35 years old, and with family history of cancer. The present data expand our knowledge of BRCA1/2 germline mutational spectrum, and it is a valuable clinical resource for genetic counseling and cancer management programs in the country.

Performance of a RAD51-based functional HRD test on paraffin-embedded breast cancer tissue

Abstract Purpose BRCA-deficient breast cancers (BC) are highly sensitive to platinum-based chemotherapy and PARP inhibitors due to their deficiency in the homologous recombination (HR) pathway. However, HR deficiency (HRD) extends beyond BRCA-associated BC, highlighting the need for a sensitive method to enrich for HRD tumors in an alternative way. A promising approach is the use of functional HRD tests which evaluate the HR capability of tumor cells by measuring RAD51 protein accumulation at DNA damage sites. This study aims to evaluate the performance of a functional RAD51-based HRD test for the identification of HRD BC. Methods The functional HR status of 63 diagnostic formalin-fixed paraffin-embedded (FFPE) BC samples was determined by applying the RAD51-FFPE test. Samples were screened for the presence of (epi)genetic defects in HR and matching tumor samples were analyzed with the RECAP test, which requires ex vivo irradiated fresh tumor tissue on the premise that the HRD status as determined by the RECAP test faithfully represented the functional HR status. Results The RAD51-FFPE test identified 23 (37%) of the tumors as HRD, including three tumors with pathogenic variants in BRCA1/2. The RAD51-FFPE test showed a sensitivity of 88% and a specificity of 76% in determining the HR-class as defined by the RECAP test. Conclusion Given its high sensitivity and compatibility with FFPE samples, the RAD51-FFPE test holds great potential to enrich for HRD tumors, including those associated with BRCA-deficiency. This potential extends to situations where DNA-based testing may be challenging or not easily accessible in routine clinical practice. This is particularly important considering the potential implications for treatment decisions and patient stratification.

Impact of pembrolizumab on ovarian function in young triple-negative breast cancer patients treated with chemo-immunotherapy

Genetic testing results in Slovenian male breast cancer cohort indicate the BRCA2 7806-2A &gt; G founder variant could be associated with higher male breast cancer risk

Abstract Purpose To analyze the prevalence of pathogenic/likely pathogenic variants (P/LPVs) in BRCA1 and BRCA2 genes in the largest cohort of Slovenian male breast cancer (MBC) patients to date and to explore a possible correlation between the Slovenian founder variant BRCA2:c.7806-2A &gt; G and predisposition to MBC. Methods We performed a retrospective analysis of 81 MBC cases who underwent genetic counseling and/or testing between January 1999 and May 2020. To explore a possible genotype–phenotype correlation, we performed additional analyses of 203 unrelated families with P/LPVs in BRCA2 and 177 cases of female breast cancer (FBC) in carriers of P/LPVs in BRCA2. Results Detection rate of P/LPVs in the BRCA1 and BRCA2 genes was 24.7% (20/81) with 95% of them in BRCA2 gene. The only two recurrent P/LPVs were BRCA2:c.7806-2A &gt; G and BRCA2:c.3975_3978dupTGCT (9 and 5 MBC cases, respectively). In families with BRCA2:c.7806-2A &gt; G, the incidence of MBC cases was higher compared to families with other P/LPVs in BRCA2; however, the difference did not reach statistical significance (17.8% vs. 8.9%, p = 0.105). BRCA2:c.7806-2A &gt; G was detected in both families with multiple cases of MBC. This splice-site variant represented a significantly higher proportion of all BRCA2 P/LPVs detected in MBC carriers compared to FBC carriers (47.4% vs. 26%, p = 0.049). Conclusion We observed a high mutation detection rate and conclude this may be due to the prevalent BRCA2:c.7806-2A &gt; G variant in Slovenia. Our results indicate a possible association between this variant and higher risk of breast cancer in males compared to other identified P/LPVs in BRCA2.

Prevalence of germline variants in consensus moderate-to-high-risk predisposition genes to hereditary breast and ovarian cancer in BRCA1/2-negative Brazilian patients

This study aimed to identify and classify genetic variants in consensus moderate-to-high-risk predisposition genes associated with Hereditary Breast and Ovarian Cancer Syndrome (HBOC), in BRCA1/2-negative patients from Brazil. The study comprised 126 index patients who met NCCN clinical criteria and tested negative for all coding exons and intronic flanking regions of BRCA1/2 genes. Multiplex PCR-based assays were designed to cover the complete coding regions and flanking splicing sites of six genes implicated in HBOC. Sequencing was performed on HiSeq2500 Genome Analyzer. Overall, we identified 488 unique variants. We identified five patients (3.97%) that harbored pathogenic or likely pathogenic variants in four genes: ATM (1), CHEK2 (2), PALB2 (1), and TP53 (1). One hundred and thirty variants were classified as variants of uncertain significance (VUS), 10 of which were predicted to disrupt mRNA splicing (seven non-coding variants and three coding variants), while other six missense VUS were classified as probably damaging by prediction algorithms. A detailed mutational profile of non-BRCA genes is still being described in Brazil. In this study, we contributed to filling this gap, by providing important data on the diversity of genetic variants in a Brazilian high-risk patient cohort. ATM, CHEK2, PALB2 and TP53 are well established as HBOC predisposition genes, and the identification of deleterious variants in such actionable genes contributes to clinical management of probands and relatives.

Thai patients who fulfilled NCCN criteria for breast/ovarian cancer genetic assessment demonstrated high prevalence of germline mutations in cancer susceptibility genes: implication to Asian population testing

Abstract Background Germline genetic mutation plays a significant role in breast cancer susceptibility. The strength of such predisposition varies among ethnic groups across the globe, and clinical data from Asian population to develop a strategic approach to who should undergo a genetic test are lacking. Methods We performed a multigene test with next generation sequencing in Thai patients whose clinical history fulfilled NCCN criteria for breast/ovarian cancer genetic assessment, consists of 306 breast cancer patients, 62 ovarian cancer patients, 14 pancreatic cancer patients and 7 prostate cancer patients. Genetic test result and clinical history were then checked with each NCCN criteria to determined detection rate for each indication. Results There were 83 pathogenic/likely pathogenic (P/LP) variants identified in 104 patients, 44 of these P/LP variants were novel. We reported a high rate of germline P/LP variants in breast cancer (24%), ovarian cancer (37%), pancreatic cancer (14%), and prostate cancer (29%). Germline P/LP variants in BRCA1 and BRCA2 accounted for 80% of P/LP variants found in breast cancer and 57% of P/LP variants found in ovarian cancer. The detection rate of patients who fulfilled NCCN 2019 guideline for genetic/familial high-risk assessment of breast and ovarian cancers was 22–40%. Conclusion Overall, the data from this study strongly support the consideration of multigene panel test as a diagnostic tool for patients with inherited cancer susceptibility in Thailand and Asian population. Implementation of the NCCN guideline is applicable, some modification may be needed to be more suitable for Asian population.

Frequency and spectrum of founder and non-founder BRCA1 and BRCA2 mutations in a large series of Russian breast cancer and ovarian cancer patients

The spectrum of BRCA1 and BRCA2 mutations in Slavic countries is characterized by a high prevalence of founder alleles. We analyzed a large data set of Russian breast cancer (BC) and ovarian cancer (OC) patients, who were subjected to founder mutation tests or full-length BRCA1 and BRCA2 analysis. The most commonly applied test, which included four founder mutations (BRCA1: 5382insC, 4153delA, 185delAG; BRCA2: 6174delT), identified BRCA1 or BRCA2 heterozygosity in 399/8533 (4.7%) consecutive BC patients, 230/2317 (9.9%) OC patients, and 30/118 (25.4%) women with a combination of BC and OC. The addition of another four recurrent BRCA1 mutations to the test (BRCA1 C61G, 2080delA, 3819del5, 3875del4) resulted in evident increase in the number of identified mutation carriers (BC: 16/993 (1.6%); OC: 34/1289 (2.6%); BC + OC: 2/39 (5.1%)). Full-length sequencing of the entire BRCA1 and BRCA2 coding region was applied to 785 women, very most of whom demonstrated clinical signs of BRCA-driven disease, but turned out negative for all described above founder alleles. This analysis revealed additional BRCA1 or BRCA2 mutation carriers in 54/282 (19.1%) BC, 50/472 (10.6%) OC, and 13/31 (42%) BC + OC patients. The analysis of frequencies of founder and "rare" BRCA1 and BRCA2 pathogenic alleles across various clinical subgroups (BC vs. OC vs. BC + OC; family history positive vs. negative; young vs. late-onset; none vs. single vs. multiple clinical indicators of BRCA1- or BRCA2-associated disease) revealed that comprehensive BRCA1 and BRCA2 analysis increased more than twice the number of identified mutation carriers in all categories of the examined women. Full-length BRCA1 and BRCA2 sequencing is strongly advised to Slavic subjects, who have medical indications for BRCA1 and BRCA2 testing but are negative for recurrent BRCA1 and BRCA2 mutations.

Cancer risk management among female BRCA1/2, PALB2, CHEK2, and ATM carriers

Identification of inherited breast cancer may guide cancer risk management. We sought to compare risk management practices across women with inherited breast cancer genes. Females with a pathogenic/likely pathogenic (P/LP) variant in BRCA1/2, PALB2, CHEK2, and/or ATM were surveyed about cancer risk management. Comparisons were made across genes. The 235 participants with P/LP variants (186 BRCA1/2, 28 PALB2, 15 CHEK2, and 6 ATM) had a median age of 54 and 61% had a prior breast cancer diagnosis. For women with P/LP variants in BRCA1/2, PALB2, and ATM/CHEK2, bilateral mastectomy (BM) rates were 79%, 61%, and 52%, and bilateral oophorectomy (BO) rates were 89%, 30%, and 37%, respectively. Among women with P/LP variants in PALB2 and ATM/CHEK2, 27% of those who had a BO had a family history of ovarian cancer. Contralateral mastectomy rates for women with P/LP variants in PALB2 and ATM/CHEK2 with unilateral breast cancer were 60% and 58%, and BM rates for those without breast cancer were 57% and 29%, respectively. These findings suggest high rates of both contralateral mastectomies among those with unilateral breast cancer and BM among those without a breast cancer diagnosis across women with P/LP variants in high and moderate penetrance breast cancer genes. BO was also often utilized for risk reduction across these women. These findings suggest potential overtreatment through risk-reducing surgery, and highlight the importance of promoting guideline-adherent, risk-appropriate care.

The implications of BRCA loss of heterozygosity (LOH) and deficient mismatch repair gene (dMMR) expression in the breast cancer of a patient with both inherited breast and ovarian cancer syndrome (BRCA2) and Lynch syndrome (MLH1)

BRCA germline pathogenic variants represent the most common inherited mechanism predisposing individuals to breast cancer, while germline pathogenic variants in one of the mismatch repair (MMR) genes represent the most common colon cancer-predisposing inherited syndrome, known as the Lynch syndrome (LS). Individuals who harbor pathogenic germline variants for both syndromes are extremely rare. Germline testing is now done routinely for patients with breast cancer and MMR testing is recommended for nearly all patients diagnosed with colon or rectal cancer (Benson et al in NCCN clinical practice guidelines in oncology (NCCN guidelines) colon cancer (Version 4.2019-November 8, 2019). www.NCCN.org, Gradishar et al in NCCN clinical practice guidelines in oncology (NCCN guidelines) breast cancer (Version 3.2019-September 6, 2019).www.NCCN.org). We report a patient with germline mutations in both BRCA2 and the MMR gene MLH1 who developed breast cancer. The breast cancer showed loss of heterozygosity (LOH) in BRCA2 (the molecular hallmark of cancers related to inheritance of a BRCA alteration) and was also deficient in mismatch repair gene protein expression (dMMR), the hallmark of LS-related cancers. We discuss the possible mechanisms of transformation that would explain the finding that the tumor showed both BRCA2 LOH and was dMMR, each of which would generally be considered a gatekeeper event for transformation of normal cells to malignancy. This report describes a patient with molecularly diagnosed breast and ovarian cancer syndrome (BRCA2) and LS. Next generation sequencing (NGS) and immunohistochemical (IHC) testing demonstrated her breast cancer to show BRCA2 LOH and to be dMMR. The patient presented represents the first reported case where both next generation sequencing (NGS) for BRCA LOH and MMR IHC testing of her breast cancer were performed and underscores the importance of using NGS including the reported mutational allelic frequency (MAF) and IHC use to predict the likely responsiveness to the recently approved PARP inhibitors and checkpoint inhibitor therapies (Robson et al in N Engl J Med 377:523-533, 2017, Lemery et al in 377(15):1409-1412, https://doi.org/10.1056/NEJMp1709968, 2017), key because the gatekeeper transforming event for tumors related to inherited cancer syndromes is loss of normal tumor suppressor gene (TSG) protein expression.

A mixed-methods study characterizing experiences of medical oncologists’ use of gonadotropin-releasing hormone agonists for treatment of breast cancer

Abstract Purpose The use of ovarian function suppression (OFS) for the treatment of breast cancer in pre-menopausal women is low and little is known about medical oncologist’ attitudes toward current guidelines pertaining to the use of OFS. This purpose of this study was to explore breast medical oncologists’ perceptions and use of gonadotropin-releasing hormone agonists as OFS for treatment of early-stage breast cancer. Methods A quantitative survey exploring experiences with OFS was distributed to medical oncologists across the USA using mailing lists available through the American Medical Association. Survey responses were characterized using descriptive statistics. Results Oncologists in this study reported high likelihood of recommending OFS for pre-menopausal women at high risk for recurrence of hormone receptor-positive early-stage breast cancer. In addition to tumor size, nodal involvement, and 21-gene recurrence scores, administration of chemotherapy was a strong surrogate for risk of recurrence. Concerns about treatment toxicity and patient hesitancy were the top barriers to OFS utilization. Oncologists also reported low confidence in their ability to determine menopausal status in the setting of amenorrhea post-chemotherapy (9% reported feeling very confident with this task) and to monitor ovarian function while on OFS. Conclusion Oncologists reported strong agreement with established guidelines for the use of OFS in the treatment of early-stage hormone receptor-positive breast cancer. However, our findings indicate a need for guidance regarding the determination of menopausal status in the setting of amenorrhea and monitoring of ovarian function.