Breast conserving therapy for central breast cancer in the United States

Breast conserving therapy (BCT) allows patients to achieve esthetic outcomes, quality of life and preserve their breast without sacrificing oncologic outcome [1‐3] and is considered as a safe treatment for early-stage breast cancer.

Central breast cancer usually refers to tumors located in the area within 2 cm of the nipple-areola complex (NAC). The research on BCT of central breast cancer were few and small sample size though the results showed acceptable recurrence rate of BCT in central breast cancer (4.8–7%) [4‐6] and the non-inferior survival outcomes [5, 7, 8] compared with non-BCT. So for central cancers breast conserving therapy was not contraindication in the guideline, but was less likely to be recommended by surgeons for reasons below: (1) careful pathologic examination of mastectomy specimens has found that more than 30% involve the nipple-areola complex [9‐11] and lumpectomies that remove the nipple-areola complex often result in poor cosmesis. (2) Perceived increase in the risk of local recurrence owing to inadequate margins. Recent stunning result was reported from a SEER data based research including 16522 central breast cancer which showed an improved survival rate for centrally located breast cancer (CLBC) receiving BCT [12]. But the early studies on the safety of BCT for CLBC [4, 13‐16] or the comparation of oncological outcomes between BCT and non-BCT [7, 8] and the recent SEER based result [12] were all constrained to T1-2 stage without taking T3-4 into account which cannot meet the increasing demand for more cosmetically acceptable breast cancer surgery. Also HER-2 status was an important factors influencing the survival outcome of breast cancer, which was not included in the recent SEER based result. So a study on the survival difference between BCT and non-BCT in central and NAC, especially in T3-4 subgroup population is urgently need.

BCT involves excision of the tumor (lumpectomy) followed by adjuvant whole breast irradiation (WBI). In order to perform BCT, it must be possible to excise the tumor to negative margins with an acceptable cosmetic outcome, the patient must be able to receive radiotherapy, and the breast must be suitable for follow-up to allow prompt detection of local recurrence. Landmark trials have established that breast conservation therapy (BCT) and mastectomy offer equivalent survival and can be viewed as equivalent treatments in early stage breast cancer (ESBC) [17, 18]. Breast conserving therapy followed by radiotherapy allows patients to achieve esthetic outcomes, quality of life and preserve their breast without sacrificing oncologic outcome [1‐3] and is considered as a safe treatment for early-stage breast cancer.

The term subareolar defined differently: Fowble et al. [7] and Haffty et al. [6] defined it as the area within 2 cm of the NAC, Haagensen shrank the distance to only 1 cm, and Simmons et al. [5] defined it as the area immediately beneath the areola. Central tumors usually refer to subareolar with some exceptions: only include NAC [19], tumors > 2 cm from areolar margin [7]. NAC malignant tumors included Paget disease, lymphoma and invasive and noninvasive breast cancers [20] and Paget disease were also a candidate for BCT [21]. In our study NAC account for 6.42% (559/8702) central and NAC patients, and the type of surgery did not correlated with location significantly (p = 0.692). But to date, the research on BCT of the NAC breast cancer is limited, so NAC breast cancer were included for further study. The early studies on the safety of BCT for CLBC [4, 13‐16] or the comparation of oncological outcomes between BCT and non-BCT [7, 8] and the recent SEER based result [12] were all constrained to T1–2 stage. So in our study, T3–4 patients were included. Wang's study compared the safety of BCT versus mastectomy for CLBC [22]. But in our study, non-breast conserving patients included not only mastectomy, but also breast reconstruction.

Our result showed a trend of BCT for CLBC and it exceed non-BCT in 2015, and the proportion of BCT was similar to whole breast cancer reported in French (57%) and English (63%) [23]. We found a higher proportion of older age, single marital status, later years at diagnosis, lower grade, lower T stage, lower N stage, ER positive status, PR positive status and HER-2 negative status to receive BCT for CLBC and those factors were thought to be associated with favored outcome.

The young breast cancer always develops more aggressive tumors at diagnosis, like hormone receptor negative, higher grade, and HER-2 negative [24] and it is not contraindication for BCT for early stage patients. In our logistic analysis, we found that there is a significantly lower proportion of a young age (< 45 yeasts old) in BCT group (6.40%) compared with non-BCT group (14.8%). With the popularization of BRCA1/2 genetic testing and the maturity of breast reconstruction surgery, more and more young women are choosing breast reconstruction and contralateral prophylactic mastectomy [25, 26]. This may be why more young women are not opting for breast conserving surgery.

The evidence for breast conserving surgery has expanded with the availability of more drugs and improved efficacy of neoadjuvant therapy. Breast conserving surgery is not limited to early stage, such as T1–T2, but can be extended to T3–4. In our research, the OS rate of central breast cancer patents was higher with breast conserving surgery than with mastectomy, which was consistent with Zhang’s results [12]. However, our study demonstrates that T3–T4 and stage III patients receiving breast conserving therapy also had higher OS (P < 0.05).

And BCT significantly reduced overall death hazard (HR 0.633; 95%CT 0.522–0.766; P < 0.001) and breast-specific death hazard (HR 0.570; 95%CT 0.435–0.746; P < 0.001) in the adjust multivariate Cox analysis. When dug deeply, we found that there is a higher proportion of older age, single marital status, more recent years at diagnosis, lower grade, lower T stage, lower N stage, ER positive status, PR positive status and HER-2 negative status to receive BCT for CLBC and those factors were thought to be associated with favored survival outcome. To eliminate the effect of those confounders on prognosis analysis, propensity match score was used. Post-match cohort showed an improved survival in BCT compared with non-BCT in central and NAC tumors.

One limitation of breast conserving surgery for central breast cancer is postoperative aesthetics. In cases of tumor involvement of the nipple-areola complex, the surgeon may remove the nipple-areola complex to ensure a negative margin. This will bring great damage to postoperative breast aesthetics. Overall, nipple areola composite reconstruction will improve patient satisfaction and confidence. With the development of plastic surgery, a variety of methods of nipple areola composite reconstruction can be achieved, including tattooing, using synthetic materials, local flaps, and grafts [27‐30]. This will make up for the shortcomings of breast conserving surgery in central breast cancer. Priya et al. demonstrated for patients with central tumor treated with neoadjuvant chemotherapy, many patients may have successfully converted to nipple-areola complex after reevaluation at the end of chemotherapy [31].

On the premise that the tumor safety and aesthetics can be achieved, breast conserving surgery for central breast cancer is a desirable option.

We recognize several limitations of this study. First of all, this study is a retrospective study with inherent flaws. Even though we use the PSM method, there will still be some biases. Secondly, because the patient's BRCA gene information is not available, it is impossible to evaluate its impact on the breast cancer surgery in the central region. Third, there is no information about postoperative complications, satisfaction and cosmetic results of breast conserving surgery in our study. Finally, the SEER database does not collect socioeconomic and baseline health information, which may be the relationship between surgical methods and survival. In the absence of prospective high-level evidence, our current large-sample retrospective study is of great significance to assess tumor safety, and more prospective studies are needed in the future.

There is an increased incidence of BCT in patients with central breast cancer. Old age and low tumor malignancy were predictors of BCT. BCT is a safe and feasible surgical procedure for central breast cancer.