Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer

The advent of affordable and rapid next-generation DNA sequencing technology, along with the US Supreme Court ruling invalidating gene patents, has led to a deluge of germline and tumor genetic variant tests that are being rapidly incorporated into clinical cancer decision-making. A major concern for clinicians is whether the presence of germline mutations may increase the risk of radiation toxicity or secondary malignancies. Because scarce clinical data exist to inform decisions at this time, the American Society for Radiation Oncology convened a group of radiation science experts and clinicians to summarize potential issues, review relevant data, and provide guidance for adult patients and their care teams regarding the impact, if any, that genetic testing should have on radiation therapy recommendations. During the American Society for Radiation Oncology workshop, several main points emerged, which are discussed in this manuscript: (1) variants of uncertain significance should be considered nondeleterious until functional genomic data emerge to demonstrate otherwise; (2) possession of germline alterations in a single copy of a gene critical for radiation damage responses does not necessarily equate to increased risk of radiation-induced toxicity; (3) deleterious ataxiatelangiesctasia gene mutations may modestly increase second cancer risk after radiation therapy, and thus follow-up for these patients after indicated radiation therapy should include second cancer screening; (4) conveying to patients the difference between relative and absolute risk is critical to decision-making; and (5) more work is needed to assess the impact of tumor somatic alterations on the probability of response to radiation therapy and the potential for individualization of radiation doses. Data on radiosensitivity related to specific genetic mutations is also briefly discussed.

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“…In this 162-patient phase 2 trial, there was a lower incidence of subsequent CBCs at a median follow-up of 58 months. 60…”

Section: Genetic Syndromes Associated With Increased Risk Of Radiatiomentioning

confidence: 99%

The Implications of Genetic Testing on Radiation Therapy Decisions: A Guide for Radiation Oncologists

Bergom

West

Higginson

et al. 2019

International Journal of Radiation Oncology*Biology*Physics

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“…[45][46][47] Recently, E. Evron et.al suggested that the addition of contralateral breast irradiation to the routine local-regional treatment was associated with a significant reduction of subsequent contralateral breast cancers and a delay in their onset. 18 In light of efficacy and safety, not only the preliminary research, but also the clinical trials proposed prophylactic mammary irradiation for prevention of CBC in BRCA mutation setting. 22,[48][49][50][51][52] Although great efforts were made to balance the patient characteristics and treatment modalities, limitations of this study mainly lay in the ascertainment biases introduced by retrospective study.…”

Section: Discussionmentioning

confidence: 99%

Outcomes and risk of subsequent breast events in breast‐conserving surgery patients with BRCA1 and BRCA2 mutation

Huang

Lang

et al. 2020

Cancer Medicine

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Purpose Previous studies provide inconsistent interpretations of the effect of inherited genetic factors on the survival and prognosis of patients with breast cancer. The aim of this study was to examine the effect of germline BRCA1 and BRCA2 mutation on survival and subsequent breast events in Chinese women who underwent breast‐conserving surgery. Methods A retrospective review of the clinical and pathological records was performed in patients diagnosed with primary invasive breast cancer between 2005 and 2018 in the cancer registry database. Clinicopathological data and data regarding treatment and outcomes, including date and site of disease progression, were collected. The survival outcomes and independent risk factors were conducted using SPSS. Results Overall, a total of 501 patients who underwent breast‐conserving surgery were identified and subjected to analyses, of which 63 cases with BRCA1 or BRCA2 mutation. The median age at diagnosis was 41 (range, 24‐74) for carriers and 37 (range, 17‐84) for noncarriers. After a median follow‐up time of 61 months (range, 8‐161) and 70 months (range, 0‐153), respectively, in carriers and noncarriers, the overall survival (P = .173) and disease‐free survival (P = .424) were not significantly different. Analogously, there was no significant difference between the two groups about the outcomes of ipsilateral breast tumor recurrence (P = .348), yet the contralateral breast cancer (CBC) was overt worse than noncarriers (P < .001). When adjusted to confounding factors, BRCA mutation was the only independent risk factors to CBC (HR = 7.89, P = .01). Conclusion In this study, BRCA mutation carriers have higher risk of CBC. And, BRCA mutation is the only independent risk factor to CBC. Therefore, intensive surveillance and follow‐up as well as more effective individual prevention are urgent. Decisions on alternatively effective prevention, especially the prevention of CBC, are urgent and should take into account patient prognosis and preferences.

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“…A non-randomized Phase II trial that evaluated prophylactic breast irradiation for the contralateral breast in BRCA mutation carriers showed reduction in the incidence of breast cancer (P= 0.011). 36…”

Section: Radiationmentioning

confidence: 99%

<p>Comparison of Patient Susceptibility Genes Across Breast Cancer: Implications for Prognosis and Therapeutic Outcomes</p>

Hasson¹,

Menes²,

Sonnenblick³

2020

PGPM

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Hereditary breast cancer syndromes affect a small (10-15% of cases) but significant group of patients. BRCA1 and BRCA2 are the most familiar and well-studied genes associated with inherited breast cancer. However, mutations in the high-penetrance genes, TP53, PTEN, CDH1, MSH1, MLH1, MSH6, PMS2, PALB2, and STK11, and in the moderate-penetrance genes, CHEK2, ATM, and BRIP1, also correlate with high lifetime risks of breast cancer and other malignancies as well. Advances in breast cancer genetics have led to an improved perception of diagnosis and screening strategies. The specific considerations and challenges involved in treating this unique population have become a fertile ground for research. Indeed, these genes and downstream molecular pathways have now become potential therapeutic targets in breast cancer patients, including those with BRCA1 or BRCA2 mutations. This review describes the variety of hereditary breast cancer genes, from their molecular origins to the prognosis and multidisciplinary clinical decisionmaking processes. Key publications and other reported recent clinical trials and guidelines are provided.

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Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer

Cited by 44 publications

References 26 publications

The Implications of Genetic Testing on Radiation Therapy Decisions: A Guide for Radiation Oncologists

The Implications of Genetic Testing on Radiation Therapy Decisions: A Guide for Radiation Oncologists

Outcomes and risk of subsequent breast events in breast‐conserving surgery patients with BRCA1 and BRCA2 mutation

<p>Comparison of Patient Susceptibility Genes Across Breast Cancer: Implications for Prognosis and Therapeutic Outcomes</p>

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