British Menopause Society consensus statement: The risks and benefits of HRT before and after a breast cancer diagnosis – Jo Marsden  , British Menopause Society – Post Reprod Health. 2019 Mar;25(1):33-37. doi: 10.1177/2053369119825716. Epub 2019 Feb 16.

In women at population risk of breast cancer (i.e. most), short-term exposure to hormone replacement therapy (i.e. up to five years’ use) for symptom relief exceeds its potential harms, including the associated, increased risk of breast cancer diagnosis. Many women and health care professionals, however, consider this to be unacceptably high, although the degree of risk conferred appears equivalent to, or less than that of, other lifestyle risk factors for this condition. In contrast, it is recommended that symptomatic women at high baseline risk due to a family history or a biopsy-confirmed high-risk benign breast condition and those with previous breast cancer should be managed initially with lifestyle changes and non-hormonal alternatives. In a minority, whose symptoms are refractory, hormone replacement therapy and or topical estrogen can be considered but prescription should only take place after a discussion between the patient, her primary health care and breast specialist teams

Contralateral breast cancer risk and endocrine therapy use in patients with ductal carcinoma in situ treated with unilateral mastectomy in the modern era – Ayat S ElSherif, Chao Tu, Stephanie A Valente Am J Surg. 2021 Mar;221(3):521-524. doi: 10.1016/j.amjsurg.2020.11.012. Epub 2020 Nov 9.

Background: In patients with ductal carcinoma in situ (DCIS), the risk of developing contralateral breast cancer (CBC) and the role of adjuvant endocrine therapy (ET) in decreasing CBC risk is not well understood.

Methods: A retrospective review was performed on patients with DCIS who underwent a unilateral mastectomy (UM) from 2000 to 2010. CBC incidence, time to CBC and disease free survival were evaluated for women who took ET versus those who did not.

Results: 176 patients underwent a UM for DCIS, 72% were ER positive and 16% of patients took ET. At a median of 12 year follow up, 15 patients experienced CBC. Women over 63 years had highest incidence of CBC. CBC risk was not different between those who took ET versus those who did not.

Conclusion: The overall incidence of CBC was 9% in our DCIS cohort and was not significantly different among patients who took ET versus those who did not.

Keywords: Contralateral breast cancer; DCIS; Ductal carcinoma in situ; Endocrine therapy.

Conclusions: Where available, DBT merits first-line use in the under 60 age group in symptomatic breast clinics, particularly in women known to have very dense breasts.

Advances in knowledge: This study is one of very few to address the accuracy of DBT in symptomatic rather than screening patients. It quantifies the diagnostic gains of DBT in direct comparison with standard digital mammography, supporting informed decisions on appropriate use of DBT in this population.

A review of the use of next generation sequencing methodologies to identify biomarkers of resistance to CDK4/6 inhibitors in ER+/HER2- breast cancer – Alberto Servetto, Fabiana Napolitano et Al. – Crit Rev Oncol Hematol. 2021 Jan;157:103191. doi: 10.1016/j.critrevonc.2020.103191. Epub 2020 Dec 9.

The development of cyclin-dependent kinases (CDK) 4 and 6 inhibitors represented a substantial breakthrough in the treatment of estrogen receptor positive (ER+), human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer. These drugs showed a significant clinical benefit in pivotal clinical trials. However, resistance eventually occurs, leading to disease progression. Next Generation Sequencing methodologies have been employed to investigate predictive biomarkers of response or resistance to CDK4/6 inhibitors. Whole exome and targeted sequencing of solid and liquid biopsies have revealed several possible genomic alterations associated with resistance. Notably, genomic alterations identified by DNA-sequencing did not fully recapitulate the entire landscape of resistance to CDK4/6 inhibitors. Gene expression analysis, such as RNA-Seq methodologies, have provided insights into transcriptional profiles and may need further application. Herein, we report the main findings derived from the use of NGS analysis in the context of resistance to CDK4/6 inhibitors in ER + breast cancer.

A Population-Based Study of Genes Previously Implicated in Breast Cancer – Chunling Hu, Steven N Hart, Rohan Gnanaolivu et Al – N Engl J Med. 2021 Feb 4;384(5):440-451. doi: 10.1056/NEJMoa2005936. Epub 2021 Jan 20.

Background: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.

Methods: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.

Results: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer.

Conclusions: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).