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Purpose of review <p>To explore historical perspectives and current management of breast cancer among women with germline pathogenic variants (PVs) in moderate and high penetrance breast cancer susceptibility genes, including <i>BRCA1</i>,<i> BRCA2</i>,<i> PALB2</i>,<i> CHEK2</i>,<i> ATM</i>, and <i>RAD51C/D.</i></p> Recent findings <p>Contralateral risk reducing mastectomy may be considered in <i>BRCA1</i>, <i>BRCA2</i>, and <i>PALB2</i> carriers, with evidence for potential survival benefit limited to women diagnosed with breast cancer under 40 years of age. For <i>ATM</i> and <i>CHEK2</i> carriers, current evidence is insufficient to routinely recommend contralateral risk reducing mastectomy outside of specific high-penetrance variants such as <i>ATM</i> c.7271T &gt; G or biallelic <i>CHEK2</i> PVs. For heterozygous <i>ATM</i> carriers, there appears to be no difference in acute or late toxicity with radiotherapy, suggesting that adjuvant radiation should be offered when clinically indicated. With respect to systemic therapy, PARP inhibitors (PARPi) have been shown to significantly improve progression-free and overall survival outcomes in <i>BRCA1/2</i> carriers with advanced or high risk early-stage breast cancer, and early data in <i>PALB2</i> carriers suggest similar efficacy. Following active treatment for breast cancer, <i>BRCA1/2</i>,<i> PALB2</i>, and <i>RAD51C/D</i> PV carriers should be referred for age-appropriate risk-reducing salping-oophorectomy.</p> Summary <p>Past and present research has helped refine local and systemic therapy recommendations for affected women with high-penetrance breast cancer susceptibility genes. Future research is required to optimize systemic and targeted therapies and individualize secondary cancer risks, particularly in moderate penetrance PV carriers.</p>

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Breast Cancer in Women with Moderate and High Penetrance Germline Pathogenic Variants in Breast Cancer Susceptibility Genes

  • 期刊论文

  • 发表日期：

    2025年10月30日

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  • Stephanie M. Wong,
  • Kelly Metcalfe

摘要

Purpose of review

To explore historical perspectives and current management of breast cancer among women with germline pathogenic variants (PVs) in moderate and high penetrance breast cancer susceptibility genes, including BRCA1, BRCA2, PALB2, CHEK2, ATM, and RAD51C/D.

Recent findings

Contralateral risk reducing mastectomy may be considered in BRCA1, BRCA2, and PALB2 carriers, with evidence for potential survival benefit limited to women diagnosed with breast cancer under 40 years of age. For ATM and CHEK2 carriers, current evidence is insufficient to routinely recommend contralateral risk reducing mastectomy outside of specific high-penetrance variants such as ATM c.7271T > G or biallelic CHEK2 PVs. For heterozygous ATM carriers, there appears to be no difference in acute or late toxicity with radiotherapy, suggesting that adjuvant radiation should be offered when clinically indicated. With respect to systemic therapy, PARP inhibitors (PARPi) have been shown to significantly improve progression-free and overall survival outcomes in BRCA1/2 carriers with advanced or high risk early-stage breast cancer, and early data in PALB2 carriers suggest similar efficacy. Following active treatment for breast cancer, BRCA1/2, PALB2, and RAD51C/D PV carriers should be referred for age-appropriate risk-reducing salping-oophorectomy.

Summary

Past and present research has helped refine local and systemic therapy recommendations for affected women with high-penetrance breast cancer susceptibility genes. Future research is required to optimize systemic and targeted therapies and individualize secondary cancer risks, particularly in moderate penetrance PV carriers.