Contralateral breast irradiation in BRCA carriers: the conundrum of prophylactic versus early treatment
Authors: P.M.P. Poortmans, O. Kaidar-Person
Journal: Annals of Oncology (2019)

In this issue of Annals of Oncology is the report of the remarkable prospective two-armed phase II trial by Evron et al., evaluating prophylactic contralateral breast irradiation for the prevention of breast cancer in high-risk BRCA-carrier cancer patients at the time of breast conserving therapy (BCT) [1.Evron E. Ben-David A.M. Goldberg H. et al.Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer.Ann Oncol. 2019; 30: 412-417Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. The authors should be applauded for this national effort, involving the entire Israeli oncological community and several external breast cancer experts to carefully plan the trial, in order to address the psychological, ethical and emotional reactions caused by the proposal to prophylactically irradiating a healthy breast. Finally, this led to the non-randomized two-armed design in which women belonging to the target population were invited to participate and, if agreed, were offered to choose for themselves prophylactic irradiation or surveillance. Women who carry a deleterious BRCA1/2 mutation have an increased lifetime risk of developing breast cancer of up to 70%. The local control rate after BCT is similar for BRCA-associated breast cancer compared with sporadic cases, on the condition that risk-reducing strategies based on adequate systemic treatment are combined with local treatments [2.Pierce L.J. Phillips K.A. Griffith K.A. et al.Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy.Breast Cancer Res Treat. 2010; 121: 389-398Crossref PubMed Scopus (141) Google Scholar, 3.Bernier J. Poortmans P. Clinical relevance of normal and tumour cell radiosensitivity in BRCA1/BRCA2 mutation carriers: a review.Breast. 2015; 24: 100-106Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. However, the risk of contralateral breast cancers remains increased (up to 30% in 10 years) in BRCA carriers, which exceeds the local recurrence rate in the affected breast [4.Pierce L.J. Levin A.M. Rebbeck T.R. et al.Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer.J Clin Oncol. 2006; 24: 2437-2443Crossref PubMed Scopus (313) Google Scholar]. To address this, risk-reducing mastectomy, with significant implications for sexuality and body image, is increasingly being proposed while BCT is proven to be safe for the affected breast. With this background, the idea of prophylactic irradiation to the contralateral breast administered simultaneously with BCT for the affected side emerged in Israel, where BRCA-associated breast cancer is common in the Ashkenazi Jewish population with 2.5% BRCA carriership [1.Evron E. Ben-David A.M. Goldberg H. et al.Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer.Ann Oncol. 2019; 30: 412-417Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 5.Warner E. Foulkes W. Goodwin P. et al.Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer.J Natl Cancer Inst. 1999; 91: 1241-1247Crossref PubMed Scopus (329) Google Scholar]. Remarkably, half of the 162 patients that agreed to participate preferred prophylactic irradiation, which was considerably higher than the one-third that was expected to do so. While it is difficult to fully understand this phenomenon, which might reflect specific sociocultural circumstances, it also highlights the particular health-related concerns that women who bear a genetic predisposition to develop breast cancer are subject to. This should be taken into consideration for the setting up of any subsequent research endeavours in this particular field, for example, by inviting representatives of the targeted population to actively contribute to the writing of a research proposal. Evron et al. [1.Evron E. Ben-David A.M. Goldberg H. et al.Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer.Ann Oncol. 2019; 30: 412-417Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar] reported that after a median follow-up of 58 months, 10 patients (12.4%) in the control arm developed contralateral breast cancer after a median of 32 months, which is significantly more and earlier than the two patients (2.5%) in the intervention arm who developed breast cancer only after 80 and 105 months, respectively (P = 0.011). There was no significant difference between the groups in any of the other end points (e.g. ipsilateral breast cancer recurrence, distant metastases, overall survival). The contralateral breast cancer risk is thereby, after 5 years, similar to that after risk-reducing mastectomy [6.van Sprundel T.C. Schmidt M.K. Rookus M.A. et al.Risk reduction of contralateral breast cancer and survival after contralateral prophylactic mastectomy in BRCA1 or BRCA2 mutation carriers.Br J Cancer. 2005; 93: 287-292Crossref PubMed Scopus (233) Google Scholar]. As more patients in the control arm had ER+ disease and were treated with adjuvant endocrine therapy, these already impressive results might even be underestimated as this endocrine therapy also reduces second breast cancer risks [7.Senechal C. Reyal F. Callet N. et al.Hormonotherapy for breast cancer prevention: what about women with genetic predisposition to breast cancer?.Bull Cancer. 2016; 103: 273-281PubMed Google Scholar]. The reduction of subsequent contralateral breast cancers and the delay in their appearance are in fact two different findings, for which long-term follow-up is definitely needed to find out whether it is not merely a postponement (which as such might also be very valuable) or true and durable prevention. This brings us to the question as to whether the prophylactic irradiation works via a mechanism that prevents the development of cancer cells or rather by active treatment of preclinical disease. Assuming the presence of preclinical 1-mm3-sized tumours in an MRI-screened breast, grown from 1 single cell to 1 000 000 cells in 5–8 years, a 50 Gy dose-equivalent irradiation will reduce the risks that this progresses into a clinically overt tumour by 97%. After this, it will again take between 8 and 12 years to develop a clinically detectable breast cancer, unless the irradiation also prevents the development of new malignant breast cells. At a mean follow-up of less than 5 years, we can therefore only confirm the early-treatment efficacy of this approach, with the recurrence interval of 80 and 105 months after intervention fitting both with the development of new tumours or radiation resistance with minor residual disease and subsequent re-growth (Table 1 and Figure 1).Table 1Calculation of age and size of CLT at both the time of initial treatment as at the time of CLT diagnosisCaseCLT breast cancer type and sizeNumber of doublings to attain CLT cancer sizeDuplication timeEstimated age at CLT cancerInterval from initial treatment to CLT cancerAge CLT cancer at initial treatmentSize CLT cancer at initial treatmentTN = triple negative; lum-B = luminal-BMonths. 1 cc = 109 cells = 30 doublingsTN = 3 months; lum-B = 4.5 months; lum-A = 6 monthsMonthsMonthsMonthsDiameter, cmControl 10, 7 cm TN G227381106(-25)0Control 2DCIS size?54Control 3DCIS size?24Control 41, 4 cm TN3039016740.4Control 51, 3 cm TN3039036540.08Control 61, 0 cm TN2938740470.05Control 7T1 size? TN42Control 80, 4 cm Lum-B254.511271050.25Control 90, 7 cm TN2738128530.08Control 10T2 size? TN19Intervention 1T2 size? TN105Intervention 20, 5 cm Lum-B264.51178037<0.001CLT, contralateral. Open table in a new tab CLT, contralateral. An unintended favourable effect might be that prophylactic contralateral breast irradiation, especially in young patients, will at least partially prevent an often-seen increasing asymmetry over the years due to progressive ptosis and (fatty) volume increase in the non-irradiated breast with ageing and weight gain. This is often wrongly interpreted as progressive shrinkage of the treated breast [8.Immink J.M. Putter H. Bartelink H. et al.Long-term cosmetic changes after breast-conserving treatment of patients with stage I-II breast cancer and included in the EORTC 'boost versus no boost' trial.Ann Oncol. 2012; 23: 2591-2598Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. Before this innovative and appealing approach could be applied outside of clinical trials, several challenges have to be taken into account. First, as 10 of the 12 contralateral breast cancers were diagnosed at a very early stage and thereby had a very good prognosis, the value of prevention could be questioned as compared with intensive follow-up, especially for patients who are treated for high-risk disease of the affected side. Second, a point of concern is that one patient developed a sarcoma within the irradiated area. However, this was a pleomorphic sarcoma in the muscle behind the breast. While it remains incontestable that this is to be considered as related to the radiation, it is disputable whether it is a real 'Radiation therapy Associated (Angio)Sarcoma' as is described in 1 per 1000 irradiated breast cancer patients [9.Rombouts AJM HJ, Hugen N, Siesling S et al. Radiation therapy associated sarcoma after breast cancer treatment: a Dutch Population-Based Study. JAMA Oncol 2019 Jan 24 [Epub ahead of print], doi: 10.1001/jamaoncol.2018.6643.Google Scholar] or whether it is a pure coincidence, maybe even related to a particular genetic predisposal as described previously [10.Kadouri L. Sagi M. Goldberg Y. et al.Genetic predisposition to radiation induced sarcoma: possible role for BRCA and p53 mutations.Breast Cancer Res Treat. 2013; 140: 207-211Crossref PubMed Scopus (33) Google Scholar]. We recommend that the demonstrated 80% reduction of contralateral breast cancer development at 5 years, combined with a delayed onset, will be tested in a larger patient population, preferably in a phase III trial. Longer follow-up is needed as well to discriminate between prophylactic and early treatment effects. Finally, if further studies confirm the results, we might even envisage testing bilateral prophylactic irradiation as risk-reducing treatment in high-risk women like BRCA carriers before any breast cancer. None declared.