Decisions regarding the selection of breast cancer therapies require an accurate determination of the ER, PgR, and HER2 expression status of the tumor, which are usually determined via biopsy to achieve a definitive diagnosis. However, a biopsy specimen represents only part of lesion and often differs from the surgical specimen. Previous reports describe ER expression concordance rates between biopsy specimens and surgical specimens as high as 92–98% and similarly high PgR concordance rates of 85–97% [13, 14]. However, the reported HER2 concordance rates are slightly lower, at 80–90% [13, 15, 16]. Moreover, anticancer therapy affects the expression of these receptors. In a meta-analysis of patients who underwent neoadjuvant chemotherapy for breast cancer, ER and PgR discordance rates of 2.5–17% and 5.9–51.7%, respectively, were reported . There are reports that it turns out to be often positive, while others report that it often turns negative. Regarding HER2, studies reported discordance rates between biopsy specimens and surgical specimens of 1.3–20% in patients who received neo-adjuvant chemotherapy (NAC) without trastuzumab and of 12–43% in whose who received NAC with trastuzumab. These data suggest that trastuzumab therapy induces a negative HER2 conversion. In our study, therefore, we targeted cases that were preoperative treatment-naïve to address the potential differences between biopsy and surgical specimens and changes due to NAC.
Some reports have described differences in the patterns of receptor expression between surgical specimens and recurrent tumor specimens [7, 8, 18-20]. A change in the ER status is observed in approximately 15% of cases, and the numbers of cases with increasing and decreasing expression are roughly equivalent. In contrast, a change in the PgR status is observed in approximately 25–40% of cases, and usually involves decreased expression. Changes in HER2 are observed in approximately 10% of cases, and more frequently tend to involve decreased expression. Consequently, some reports describe a change in breast cancer subtype to TNBC in recurrence, and these cases tend to have a worse prognosis than those with primary TNBC [7, 8]. In our study, we also compared the receptor expression patterns between surgical specimen and corresponding biopsies of recurrent tumors, which involved the local or regional lymph nodes in 90% of cases. The primary tumor type was HRBC in 76.0% of cases, and the frequencies of change in the ER, PgR, and HER2 statuses between the surgical and recurrent specimens were similar to those in previous reports.
In vitro experiments have demonstrated the ability of tobacco components to increase the proliferative capacity and induce malignant transformation in breast cancer cells [4-6], and various reports have described an association between ER expression and smoking in clinical practice [21-26]. However, few reports have explored the potential relationship between HER2 expression and smoking in breast cancer. Notably, we observed a significant correlation between smoking and a positive conversion of HER2 in our study. Although smoking is a known etiologic factor in lung cancer, an interesting potential correlation between HER2 mutation and lung cancer in never-smokers has attracted clinical attention [27, 28]. However, in vitro experiments have demonstrated the ability of tobacco components to induce HER2  and amplify the expression of EGFR and HER3 [29, 30]. Crosstalk has been identified within the HER family, and potentially the amplification of another HER family member may enhance the expression of HER2 [31, 32]. In the future, it is necessary to examine the biological changes caused by tobacco components in breast cancer cells using immunohistochemical staining, genetic analysis, and protein quantification in vitro.
The choice of treatment after recurrence varied among the cases in our study, as some patients underwent excision of the recurrent lesions and others began anticancer therapy. Consequently, an evaluation of prognosis was challenging. However, we found that a negative hormone receptor conversion, positive HER2 conversion, and change of the intrinsic breast cancer subtype appears to reduce the DFS. However, smokers in our study appeared to have a better DFS and OS, possibly because the switch from ER+/HER2- to ER+/HER2+ breast cancer in most smokers enabled the administration of more effective drug treatment.
This study had a few limitations of note. Particularly, we only obtained data about the smoking history up to surgery, and the use of an interview to collect these data may have introduced bias. Although we agree that the postoperative smoking status is important, some reports suggest that the total smoking history is more important than the current smoking status with respect to carcinogenesis and recurrence [33, 34]. Moreover, we were not able to reach clear conclusions about receptor expression patterns on distant metastases, as most recurrences occurred in local or regional lymph nodes. However, the identification of a correlation between smoking and the positive conversion of HER2 at recurrence suggests that appropriate treatment may not have been administered to patients with distant metastases. We must therefore consider the possible link between smoking and HER2 amplification when evaluating cases in which a biopsy of a distant metastasis cannot be performed.