HER-2 positive breast cancer is associated with an increased risk of positive cavity margins after initial lumpectomy

DNA microarray profiles have been used to classify breast tumors into distinct biologic subtypes [1, 2]. This testing may not often be feasible in a clinical setting, and these subtypes can be approximated by the expression of immunohistochemically-defined biological markers, such as the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), to classify tumors as luminal A (ER⁺ or PR⁺ and HER-2⁻), luminal B (ER⁺ or PR⁺ and HER-2⁺), HER-2⁺ (ER⁻ and PR⁻ and HER-2⁺), or triple-negative (TN) (ER⁻ and PR⁻ and HER-2⁻) subtypes [3]. Most reports show that the luminal A subtype is associated with the best prognosis, whereas significantly worse prognoses have been observed for the HER-2 and TN subgroups [4‐6].

Randomized trials have validated breast-conserving surgery (BCS) as the standard treatment for early stage breast cancer (BC) [7, 8]. Minimizing local recurrence (LR) in the breast is very important in clinical settings because LR is associated with reduced survival and emotional distress [9]. The status of the surgical margin has been shown to be an independent predictor of LR [10, 11]. In a review including 34 related studies, LR was increased in cases involving a persistent, positive margin [12]. Negative margins should be achieved during BCS as recommended by the National Comprehensive Cancer Network guidelines.

Many studies have demonstrated that patients with HER-2 overexpression and TN BCs are at increased risk of developing LR following BCS [6, 13, 14]. Does the higher risk of LR in the two subtypes result from an increased microscopic invasive tumor burden that could be indicated by margin status after lumpectomy? We have no definite answer at present. Positive margins were reported to be significantly associated with large tumor size, young age, positive nodes, presence of lymphovascular invasion (LVI), and presence of an extensive intraductal component (EIC) [15‐17]. In addition to the above analyzed clinical and pathologic variables, molecular phenotype may be a relevant factor of positive margins. The purpose of this study was to determine whether BC subtype approximation is associated with positive margins after initial lumpectomy and the extent of initial surgery that should be considered according to molecular subtypes.

In this study, we determined whether BC subtype, as approximated by ER, PR, HER-2, and Ki67, was associated with positive CMs of 1,032 consecutive women who underwent lumpectomies for early stage invasive BC. Compared to all other subtypes, the HER-2 positive subtype was an independent predictor of positive CMs (OR = 2.60, P <0.001) and an independent prognostic factor for LR (P = 0.016).

Many reports have shown that patients with the HER-2 subtype have an increased risk for LR after BCS and radiotherapy (RT) [6, 14]. In our study we found that HER-2 positive patients had a significantly higher recurrence risk, which is consistent with above studies. Randomized trials have demonstrated that the addition of trastuzumab to chemotherapy decreases LR by approximately 50% compared to treatment with chemotherapy alone [29]. The mechanisms underlying the high rate of LR in patients with the HER-2 subtype have not been conclusively determined. In a study, HER-2 status was reported to be the only primary tumor characteristic that correlated with the presence of circulating tumor cells [31]. Some groups have found that circulating tumor cells in operable BC patients are associated with worse prognosis [32]. In another study, patients with the HER-2 subtype were found to be more likely to have multicentric disease [33]. It was also reported that patients with the HER-2 subtype may be relatively resistant to post-lumpectomy RT [34, 35]. The above studies may partly explain the high rate of LR. Our finding that the HER-2 subtype was associated with an increase in positive CMs may lead to interpreting HER-2 BC with multicentric disease, which would result in increased residual microscopic tumors and higher LR to some extent. The follow-up results in our study showed that the HER-2 positive cancer had the highest LR, and maybe it is a reasonable verification of the above theory.

In a previous study, luminal BCs were reported to have a better prognosis [4, 5]. Interestingly, increased LR with the luminal B subtype among young women after BCS has been reported [35, 36]. In the current study, 40.6% of patients between the ages of 36 to 50 years with the luminal B subtype had positive CMs, which was higher than in the >50 years subgroup. Using univariate analysis with the luminal A subtype as the baseline, the luminal B subtype was associated with an increased rate of positive CMs, with an odds ratio of 2.03 (95% CI: 1.34–3.08, P = 0.001). This finding may partially explain the increased LR with the luminal B subtype. The mechanisms are still not well understood and need further study.

In our study, the TN subtype had a low rate of positive CMs, and the result did not seem to coincide with the higher LR of the TN subtype reported by most papers [4, 37, 38]. We observed the clinicopathologic features of the TN subgroup in the present study and found that this low rate of positive CMs may be related to the fact that most TN patients had T1 stage tumors (60.7%), less presence of LVI (TN vs. HER-2: 10.7% vs. 14.3%), and EIC (TN vs. HER-2: 4.1% vs. 22.6%). TN patients with large tumors may have received immediate mastectomies or neoadjuvant chemotherapy and would have thus been excluded from our study. This finding may reflect selection bias, but we have performed multivariate analyses to adjust for the confounding factors.

Our univariate analysis showed that the BC subtype, the presence of EIC or LVI, histopathology subtype, and pN stage were significantly associated with positive CMs. This result was not completely consistent with a previous study [20]. Cao et al. [20] reported that younger patient age, higher number of positive LMs, higher tumor grade, and the presence of EIC were predictive of residual carcinoma in CM specimens. In our study, age and high tumor grade were not predictive factors of positive CMs. Several previous studies have also demonstrated that the presence of EIC [17, 20] and larger tumor size [22, 39] were predictive factors for positive CMs. So far, we have only found one paper, reported by Sioshansi et al. [39], that was specifically looking for associations of different BC subtypes with the risk of residual tumors. Sioshansi et al. [39] showed that age (P = 0.003), tumor size (P <0.001), LVI (P = 0.007), nodal status (P <0.001), and TN subtype (P = 0.006) were associated with an elevated risk of residual invasive cancer by univariate analysis [39]. In our univariate analysis, EIC (P <0.001) was also an important predictive component of positive CMs, and this was not shown in the previous study. Using multivariable analysis, only nodal status (OR = 3.06, 95% CI: 1.77–5.30, P <0.001), TN status (TN vs. non-TN, OR = 3.28, 95% CI: 1.56–6.89, P = 0.02), and tumor size (tumor size >2.0 cm vs. <1.0 cm, OR = 3.49, 95% CI: 1.65–7.38, P = 0.001) maintained statistical significance on multivariate analysis [39]. However, tumor size was not a significant predictive factor associated with positive CMs in our multivariate analysis. EIC (OR = 2.58, 95% CI: 1.53–4.32, P <0.001), pN stage (N3 vs. N0: OR = 3.92, 95% CI: 1.60–9.62, P = 0.003), and HER-2 subtype (HER-2 vs. luminal A: OR = 2.60, 95% CI: 1.48–4.57, P <0.001) were significantly correlated with positive CMs. The difference between associated BC subtypes may be due to the following: i) Classification by different immunohistochemical markers. In previous studies, approximated molecular phenotypes were defined by ER, PR, and HER-2, which was different from our new classification. On the basis of recent data suggested by the 12th St. Gallen International Breast Cancer Conference (2011) Expert Panel, the Ki67 index was used in our study, which additionally discriminated partial luminal B patients from luminal A patients. The use of the Ki67 index is unique to this study. ii) Distribution of BC subtypes. Sioshansi et al. [39] reported that 73.5% of patients in their study were luminal A, 9.5% were luminal B, 4.5% were HER-2 enriched, and 12.5% were TN. In our study, 52.3% were luminal A, 14.9% were luminal B, 12.8% were luminal-HER-2, 8.0% were HER-2, and 11.8% were TN.

Among different age groups, positive rate of CMs in different molecular subtypes is not clear yet. We analyzed positive rates of CMs (including invasive cancer and carcinoma in situ) by age quartile and BC subtype in the current study. Women aged ≤35 years with BC are reported to have a poor prognosis and for most women, and menopause happens around age 50. According to this, we divided patients into three groups. In the youngest age quartile (≤35 years), the positive CM rate demonstrated no significant difference (P = 0.204). In contrast, the quartile containing ages 36 to 50 years had positive CM rates of 40.6% and 40.9% in luminal B and HER-2 subtypes, respectively (P <0.001), and the quartile with patients older than 50 years had a positive CM rate of 42.5% with the HER-2 subtype, which reached statistical significance (P = 0.001). Thus, younger age (≤35 years) was not a risk factor for positive CMs in our study.

The risk of residual disease, including carcinoma in situ and invasive cancer (residual disease, including carcinoma in situ alone, was excluded from one study [39]), after lumpectomy has been examined in many studies [24, 40]. In recent decades, positive re-excision rates from 17% to 39% have been reported [20, 41‐43]. In our current series, 20.3% (209/1,032) of patients had positive CMs, including carcinoma in situ and invasive cancer. This result was similar to those of previously published literature. For a comprehensive assessment, we also evaluated the positive CM rate with carcinoma in situ or invasive cancer alone using multivariate analysis. The positive rates were 9.6% (87/910, CMs with carcinoma in situ alone) and 12.9% (122/945, CMs with invasive cancer alone). For patients with positive CMs, including carcinoma in situ, EIC (P <0.001) and BC subtypes (HER-2 vs. luminal A: P <0.001; luminal B vs. luminal A: P = 0.008; luminal-HER-2 vs. luminal A: P = 0.032, Table 4) showed a significant association with positive CMs. For patients with positive CMs, including invasive cancer alone, histological subtype (presence of DCIS component vs. IDC, P = 0.040; invasive lobular carcinoma vs. IDC, P = 0.031) and pN stage (N1 vs. N0: P = 0.003; N3 vs. N0: P <0.001, Table 4) showed statistical correlation with positive CMs. BC subtype was no longer a relevant factor, which was not consistent with Sioshansi et al. [39].

There are several inherent limitations to this study. i) Although many surgeons increasingly prefer to use CMs for margin assessment, without information from long-term clinical follow-up, it is not clear whether CMs or LMs are superior. We used only the CM method without corresponding LM section analysis. ii) This is a single-center study, and the population was not representative of Chinese or Asian demographics. iii) BC subtypes approximated according to ER, PR, HER-2, and Ki67 are only a substitute for genotype-based molecular BC subtypes. Further studies will be needed to confirm the findings based on these new definitions.

In summary, although there are potential limitations to this study, the findings showed that that the poor prognosis of the HER-2 subtype is due to increased residual microscopic tumor burden after lumpectomy. More clinical trials will be required to confirm our conclusion. This information may help surgeons to choose the most appropriate surgical treatment for each patient. Further study and follow-up data are required to confirm the findings from our study. Oncoplastic breast surgery and an increased “boost” in radiotherapy may be good choices for patients with the HER-2 subtype to reduce the microscopic tumor burden and to improve prognosis and cosmetic results.