Breast cancer is the most common cancer diagnosed among women worldwide and more than half are diagnosed above the age of 60 years. Life expectancy is increasing and the number of breast cancer cases diagnosed among older women are expected to increase. Undertreatment, mostly due to unjustifiable fears of advanced-age and associated comorbidities, is commonly practiced in this group of patients who are under-represented in clinical trials and their management is not properly addressed in clinical practice guidelines. With modern surgery and anesthesia, breast surgeries are considered safe and is usually associated with very low complication rates, regardless of extent of surgery. However, oncoplastic surgery and management of the axilla can be tailored based on patients'-and disease-related factors. Most of chemotherapeutic agents, along with targeted therapy and anti-Human epidermal growth factor receptor-2 (HER2) drugs can be safely given for older patients, however, dose adjustment and close monitoring of potential adverse events might be needed. The recently introduced cyclin-D kinase (CDK) 4/6-inhibitors in combination with aromatase inhibitors (AI) or fulvestrant, which changed the landscape of breast cancer therapy, are both safe and effective in older patients and had substituted more aggressive and potentially toxic interventions. Despite its proven efficacy, adjusting or even omitting adjuvant radiation therapy, at least in low-risk older patients, is safe and frequently practiced. In this paper, we review existing data related to breast cancer management among older patients across the continuum; from resection of the primary tumor through adjuvant chemotherapy, radiation and endocrine therapy up to the management of recurrent and advanced-stage disease.

Purpose Cyclin dependent kinase (CDK) 4/6 inhibitors (palbociclib, ribociclib and abemaciclib) modulate endocrine resistance and are integral treatment for patients with advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Since their approval, CDK4/6 inhibitors are widely used in clinical practice. Thromboembolic events (TEE) were not a major issue in patients treated on clinical trials utilizing these agents. However, conflicting data started to emerge describing higher than expected rates of both arterial and venous thrombosis in patients treated with CDK4/6 inhibitors. In this study, we report our experience on TEE in patients treated with one of these agents (ribociclib) in real-world settings. Patients and Methods All consecutive patients with metastatic breast cancer (mBC) treated with ribociclib combined with letrozole or fulvestrant were retrospectively reviewed. All episodes of radiologically confirmed arterial or venous thrombosis were recorded. TEE was considered ribociclib-related if diagnosed while patients are on the drug, or within 4 weeks after the last dose. Results A total of 305 patients, median age (range), 49 (22–87) years were enrolled. All patients had metastatic disease, and most (n=241, 79.0%) were with visceral metastasis. Ribociclib was used for a median duration of 7 months (range: 1–45) and was used beyond the first-line setting in 110 (35.9%) patients. TEE were confirmed on 6 (1.97%) patients; 3 were pulmonary embolism, 2 cerebral venous sinus thrombosis (CVST), and one case of limb ischemia and all were symptomatic. Similar rates of TEE were noted prior to initiation, and after stopping ribociclib. Conclusion In real-world settings, breast cancer patients treated with ribociclib, combined with aromatase inhibitors or fulvestrant, may not be at higher risk for thromboembolic events. However, unusual sites of thrombosis, like CVST, may raise some concerns.

Most of breast cancer cases are sporadic; however, 15-20% are associated with family history, and some are inherited. Among those, deleterious mutations in BRCA1 and BRCA2 tumor suppressor genes are the most commonly encountered pathogenic germline variants (PGVs). Given the availability and affordability of multi-gene panel sequencing technologies, testing for PGVs is commonly practiced. With our enhanced understanding of cancer genetics and specific molecular alterations, the better acceptance of risk-directed screening and prevention, and the recent introduction of novel targeted therapies, management of BRCA-positive breast cancers is taking a new direction, focusing more on risk-reducing interventions, including mastectomy and salpingo-oophorectomy, and incorporating special treatment regimens, including platinum-based chemotherapy, and the recently-introduced PARP (poly (ADP)-ribose polymerase) inhibitors. Given the recent advances in reproductive technology and molecular medicine, younger women with PGVs may have the option of embryo selection through preimplantation genetic testing and diagnosis, thus preventing the potential transmission of the implicated genes to the next generations. In this review, we cover the clinical implications of identifying a pathogenic germline mutation in BRCA1 and BRCA2 genes in breast cancer patients, and their relatives, across the continuum of care -from cancer prevention and early detection, through active treatment and up to survivorship issues.

Background Genetic testing for at-risk patients with breast cancer should be routinely offered. Knowledge generated may influence both treatment decisions and cancer prevention strategies among the patients themselves and their relatives. In this study, we report on the prevalence and patterns of germline mutations, using commercially available next-generation sequencing (NGS)-based multi-gene panels (MGP). Patients and Methods Consecutive at-risk breast cancer patients, as determined by international guidelines, were offered germline genetic testing using a 20-gene NGS-based panel at a reference lab. Samples of peripheral blood were obtained for DNA extraction and genetic variants were classified as benign/likely benign (negative), pathogenic/likely pathogenic (positive) or variants of uncertain significance (VUS). Results A total of 1310 patients, median age (range) 43 (19–82) years, were enrolled. Age ≤45 years (n = 800, 61.1%) was the most common indication for testing. Positive family history of breast, ovarian, pancreatic or prostate cancers, and triple-negative disease were among the common indications. Among the whole group, 184 (14.0%) patients had pathogenic/likely pathogenic variants; only 90 (48.9%) were in BRCA1 or BRCA2 , while 94 (51.9%) others had pathogenic variants in other genes; mostly in APC, TP53, CHEK2 and PALB2 . Mutation rates were significantly higher among patients with positive family history (p = 0.009); especially if they were 50 years or younger at the time of breast cancer diagnosis (p < 0.001). Patients with triple-negative disease had relatively higher rate (17.5%), and mostly in BRCA1/2 genes (71.4%). Variants of uncertain significance (VUS) were reported in 559 (42.7%) patients; majority (90.7%) were in genes other than BRCA1 or BRCA2 . Conclusion Pathogenic mutations in genes other than BRCA1/2 are relatively common and could have been missed if genetic testing was restricted to BRCA1/2 . The significantly high rate of VUS associated with multi-gene panel testing can be disturbing.

Background: Genetic testing and genetic counseling for patients with breast cancer are routinely practiced as recommended by many professional societies and international guidelines including the National Comprehensive Cancer Network (NCCN). In addition to its major impact on cancer prevention, knowledge generated may impact cancer management, too. In this study, we evaluate the prevalence and patterns of germline mutations among at-risk breast cancer patients using commercially available next generation sequencing (NGS)-based multi-gene panel (MGP). Patients and Methods: Consecutive at-risk breast cancer patients, as recommended by the NCCN guidelines, were offered genetic testing using a 20-gene NGS-based panel performed at a reference genetic lab. Prior to testing, patients underwent extensive counseling by one of the investigators or their primary oncologist. Genetic variants were classified as benign or likely benign (negative), pathogenic or likely pathogenic (positive) or variants of uncertain significance (VUS). Clinical and pathological data were obtained from patients’ medical records, and detailed familial lineage for three generations was obtained by a cancer genetic counselor. Results: Between November 2019 and March 2021, a total of 714 patients were enrolled, the median age (range) was 39 (19-78) years. Among the whole group, 91 (12.7%) patients had pathogenic/likely pathogenic variants, mostly in BRCA1 and BRCA2 (n=50, 54.9%). However, 41 (45.1%) had pathogenic variants in genes other than BRCA1 or BRCA2; mostly in TP53, PALB2, CHECK2, BRIP2, ATM and MSH6.Mutation rates were significantly higher among a group of 182 women diagnosed at any age, with one or more close relatives with breast cancer (18.7% compared to 10.7%, p=0.007), and among 287 younger patients (diagnosed at age ≤ 50 years) with one or more close relatives with breast, ovarian, pancreatic, or prostate cancer (Gleason score ≥7); 17.1% vs. 9.8%, p=0.008. Additionally, patients with triple-negative disease (n=92) had higher pathogenic mutations; 17.4% vs. 12.1%, p=0.03. Variants of uncertain significance (VUS) were observed among 213 (29.8%) and majority (n=160, 75.1%) were in genes other than BRCA1 or BRCA2. Conclusions: Pathogenic mutations in genes other than BRCA1 or BRCA2 are relatively common and could have been missed, if genetic testing was restricted to BRCA1 or BRCA2. Patients with triple-negative disease and those with additional positive family history, have the highest mutation rates. On the other hand, expanding genetic testing using MGP resulted in a significantly higher rate of VUS, a finding that may increase the anxiety of patients and physicians, alike. Citation Format: Hikmat Abdel-Razeq, Rama Almasri, Lama Abujamous, Mahmoud Al-Masri, Majd Hamed Allah, Faris Tamimi, Sarah Edaily, Fawzi Abuhijla, Osama Salama, Hazem Abdulelah, Rayan Bater. Guideline-based multi-gene panel (MGP) testing for germline pathogenic variants among patients diagnosed with breast cancer: Regional perspectives [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-06.