Repeat breast-conserving surgery (BCS) for in breast tumor recurrence after initial BCS for ductal carcinoma in situ

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer with unpredictable behavior. Randomized trials show that adjuvant radiotherapy (RT) reduces local recurrence risk after adequate excision (1). Recurrent disease after breast-conserving surgery (BCS) and RT has traditionally been treated with total mastectomy; however, this paradigm has recently been challenged (2).

Diskin et al. have recently reported no significant differences in breast cancer-specific survival (BCSS) or overall survival (OS) between mastectomy and repeat BCS (re-BCS) for recurrence after initial BCS for DCIS. Notably, patients undergoing re-BCS were likely undertreated with RT, with only 22% receiving primary RT and 44% receiving secondary RT, leaving 41% without any RT despite undergoing re-BCS. Additionally, only 5% of these patients received endocrine therapy compared to 11% in the mastectomy group. The omission of RT cannot be explained by tumor risk profile or patient age, as 59% of initial DCIS cases in the re-BCS group had necrosis, and the average age was 59 (48–68 years). It is plausible that the OS and BCSS in the re-BCS group were compromised by insufficient RT (2).

There is growing evidence that BCS plus RT is associated with superior OS compared to mastectomy for DCIS. Onitilo et al. reported an OS benefit for BCS with RT compared to mastectomy in 5,335 DCIS patients, with 5-, and 10-year OS rates of 92.9% vs. 88.3%, and 80.9% vs. 67.2%, respectively (3). In a large cohort study of over 140,000 DCIS patients, Giannakeas et al. found an adjusted hazard ratio for mortality of 0.75 [95% confidence interval (CI): 0.65–0.87; P<0.001] for BCS with RT versus mastectomy in a matched cohort of 29,865 pairs, despite fewer local recurrences with mastectomy (4).

In the lumpectomy cohort, RT reduced breast cancer mortality by 0.27% at 15 years with greater reductions in women under 50 (1.59%), Black women (0.87%), and those with ER-negative cancers (0.57%). The survival benefit was attributed to the local and systemic effects of RT. However, RT can be safely omitted after BCS for small, low-grade DCIS with adequate surgical margins (4,5).

Patterns of invasive recurrence differ between mastectomy and BCS for DCIS. Pawloski et al. found that patients initially treated with mastectomy had more regional or distant metastases compared to those treated with BCS. Of the recurrences after mastectomy, 88% were regional or distant, while only 7% of recurrences in the BCS group were regional or distant (P<0.001) (6). This difference is likely due to the absence of breast tissue in the mastectomy group and the higher-risk profile of the initial DCIS.

Radiation therapy affects circulating tumor cells (CTCs) through both direct and indirect mechanisms. The direct effect occurs when CTCs pass through the breast during radiation, leading to the destruction of some cells and the release of tumor-associated antigens that elicit an immune response. The indirect mechanism involves the immune response generated from radiation’s effect on the breast tumor microenvironment and any residual tumor cells within the treated breast (7).

We have recently proposed a hypothesis to explain why BCS with RT, and re-BCS, may outperform mastectomy for invasive breast cancer (7). Our theory, based on the homing phenomenon of CTCs, can also be applied to DCIS. Research, including our own (8), shows that many patients with pure DCIS harbor CTCs and according to our hypothesis these cells are inclined to return to the original breast when activated. In cases of mastectomy, the absence of the breast forces these cells to evolve further, acquiring invasive capabilities and seeking metastatic sites elsewhere, increasing the likelihood of regional or distant metastatic recurrence. Conversely, patients undergoing BCS are more prone to in-breast tumor recurrence (IBTR), which accounts for the higher incidence of local recurrence after BCS for DCIS. Therefore, as observed in invasive breast cancer (7,9), it is feasible that re-BCS for IBTR after initial DCIS diagnosis could potentially lead to better BCSS and OS, provided that patients receive adequate RT.

Therefore, in the era of risk-adapted treatment optimization, re-BCS should be considered for patients developing IBTR after initial DCIS following a multidisciplinary discussion, with the reassurance that it does not compromise BCSS or OS compared to mastectomy.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-438/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-438/coif). K.M. has received honoraria for offering academic and clinical advice to Merit Medical and QMedical Corporations; he has stocks in HCA Healthcare, Datar Genetics, and OncoBotanica, and one of the studies he participated in was funded by a research grant provided by Breast Cancer Charity. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Mokbel K. Towards optimal management of ductal carcinoma in situ of the breast. Eur J Surg Oncol 2003;29:191-7. [Crossref] [PubMed]
2. Diskin B, Sevilimedu V, Morrow M, et al. Management of Ipsilateral Breast Tumor Recurrence Following Breast Conservation Surgery for Ductal Carcinoma In Situ: A Data-Poor Zone. Ann Surg Oncol 2024;31:8843-7. [Crossref] [PubMed]
3. Onitilo AA, Engel JM, Stankowski RV, et al. Survival Comparisons for Breast Conserving Surgery and Mastectomy Revisited: Community Experience and the Role of Radiation Therapy. Clin Med Res 2015;13:65-73. [Crossref] [PubMed]
4. Giannakeas V, Sopik V, Narod SA. Association of Radiotherapy With Survival in Women Treated for Ductal Carcinoma In Situ With Lumpectomy or Mastectomy. JAMA Netw Open 2018;1:e181100. Erratum in: JAMA Netw Open 2019;2:e1911052. [Crossref] [PubMed]
5. Mokbel K, Cutuli B. Heterogeneity of ductal carcinoma in situ and its effects on management. Lancet Oncol 2006;7:756-65. [Crossref] [PubMed]
6. Pawloski KR, Tadros AB, Sevilimedu V, et al. Patterns of invasive recurrence among patients originally treated for ductal carcinoma in situ by breast-conserving surgery versus mastectomy. Breast Cancer Res Treat 2021;186:617-24. [Crossref] [PubMed]
7. Mokbel K. Unlocking the Power of the Homing Phenomenon: Why Breast Conserving Surgery Outshines Mastectomy in Overall Survival. Clin Breast Cancer 2024;24:85-92. [Crossref] [PubMed]
8. Crook T, Leonard R, Mokbel K, et al. Accurate Screening for Early-Stage Breast Cancer by Detection and Profiling of Circulating Tumor Cells. Cancers (Basel) 2022;14:3341. [Crossref] [PubMed]
9. Tollan CJ, Pantiora E, Valachis A, et al. A Systematic Review and Meta-Analysis on the Role of Repeat Breast-Conserving Surgery for the Management of Ipsilateral Breast Cancer Recurrence. Ann Surg Oncol 2022;29:6440-53. [Crossref] [PubMed]