Neoadjuvant chemotherapy is a pivotal component in the management of breast cancer, with its efficacy significantly correlated to the molecular subtype and stage of the disease. It is administered to approximately 17–40% of patients with early-stage breast cancer, aiming for the optimal outcome of a pathological complete response (pCR) [5, 6]. Nonetheless, the pCR rates after neoadjuvant chemotherapy vary across different molecular subtypes of breast cancer. Reports suggest that HER-2 + patients have a pCR rate of around 40%, triple-negative breast cancer exhibits a pCR rate of approximately 23%, and HR + /HER-2- breast cancer has a notably low pCR rate of only 9.1% [7,8,9,10]. Despite these differences, there is a paucity of research on the prognostic implications post-pCR across these molecular subtypes. Our study, utilizing a comprehensive retrospective analysis of the SEER database, indicates that HR + /HER-2 + patients exhibit the best OS and CSS following pCR achieved through neoadjuvant treatment, outperforming other molecular subtypes. Conversely, the prognosis for HR + /HER-2- patients is significantly poorer.
Nadia Howlader et al. conducted a retrospective analysis through the SEER database on the overall 4-year survival rate of 196,094 female patients with invasive breast cancer from 2010 to 2014. They found that the survival rates for patients with HR + /HER2- and HR + /HER2 + subtypes were similar, at 92.5% versus 90.3% respectively. Moreover, among patients with initial stage IV disease, those with the HR + /HER2 + subtype had a better survival rate compared to those with the HR + /HER2- subtype (45.5% vs 35.9%) [11]. The Kaplan Meier survival curve in our study indicated that patients with invasive ductal carcinoma who received neoadjuvant chemotherapy and achieved the pCR had a higher CSS rate in the HR + /HER-2 + group. This could be associated with the use of targeted treatment drugs for patients with HER-2 + . In the KRISTINE phase 3 trial, a pathological complete response was achieved by 55.7% in the docetaxel, carboplatin, and trastuzumab plus pertuzumab neoadjuvant therapy group [12]. In the CLEOPATRA clinical trial, 402 patients with HER-2 + metastatic breast cancer treated with Pertuzumab, Trastuzumab, and Docetaxel had a median survival of nearly 5 years (57.1 months), significantly exceeding the early estimated median survival of about 2 years [13]. In addition, other drugs targeting HER-2, such as Lapatinib, Pyrotinib, and T-DM1, have been incorporated into clinical guidelines and practice. These drugs can be combined with endocrine therapy, chemotherapy, or each other, making the treatment options for HR + /HER2 + subtypes more extensive than those for other types of breast cancer. This might explain the higher OS and CSS we observed.
Several studies report that HER-2 + and triple-negative patients have a high neoadjuvant response rate, achieving significant survival benefits after reaching pCR [14,15,16]. However, HR + /HER-2- early invasive cancer patients show a low response rate to neoadjuvant chemotherapy, and clinicians often prioritize surgery, followed mainly by endocrine therapy postoperatively [17]. Although HR + /HER-2- is the most common type of invasive breast cancer clinically, accounting for 60–70% of all breast cancer classifications [18]. Unlike other subtypes of breast cancer, the recurrence risk of HR + breast cancer extends from 5 years post-diagnosis to at least 20 years, with some patients potentially relapsing even 30 years after diagnosis [19]. Despite HR + /HER-2- breast cancer having a higher endocrine treatment response rate, the 5-year tumor-specific mortality rate still exceeds 30% in some high-recurrence risk patients [20]. The recurrence and metastasis of HR + /HER-2- breast cancer is closely related to intertumoral heterogeneity and endocrine resistance [21]. To enhance the precision treatment effectiveness for HR + /HER2- breast cancer, Zhi-Ming Shao et al. utilized multi-omics technologies to classify HR + /HER-2- type invasive breast cancer into four subtypes: canonical luminal subtype (SNF1), immunogenic subtype (SNF2), proliferative subtype (SNF3), RTK-driven subtype (SNF4). It was found that among these four subtypes, patients with the RTK-Driven type had the worst prognosis, with endocrine therapy being almost ineffective [22]. This may also result in a subset of HR + /HER-2- patients having a poor prognosis despite achieving pCR through neoadjuvant chemotherapy, followed by standardized surgery and endocrine therapy.
In addition to molecular subtypes, lymph node staging is also an important prognostic risk factor [23, 24]. Approximately 30% of breast cancer patients experience regional lymph node (LN) metastasis, which is associated with early recurrence and poor clinical prognosis. Elevated lymph node staging is frequently correlated with worse prognosis [25, 26]. Similar to previous studies, in the multivariable analysis of tumor-specific survival for invasive ductal carcinoma in this study, the hazard ratio for N3 significantly increased compared to N0 (HR = 6.17, 95%CI:4.28–8.89, P < 0.05), this suggested a deterioration in prognosis with increasing N staging. After neoadjuvant chemotherapy, patients whose axillary lymph nodes reached pCR had a better prognosis than those who did not reach pCR. However, there are differences in the pCR rates of axillary lymph nodes among patients with invasive breast cancer of different molecular subtypes. Sanaz Samiei et al. conducted a pooled analysis, encompassing 33 studies and a total of 57,531 patients. The results showed that the pCR rate in axillary lymph nodes was lowest for the HR + /HER-2- subtype of breast cancer, at 16%. For HR + /HER-2 + , HR-/HER-2 + , and HR-/HER-2- subtypes, the axillary lymph node pCR rates were 45%, 57%, and 47% respectively [27]. Rene Flores et al. discovered that, in comparison to other molecular subtypes, patients diagnosed with HR + /HER-2- breast cancer exhibited the greatest risk of their axillary lymph nodes failing to achieve a pathological complete response (pCR) following neoadjuvant chemotherapy (OR = 1.57, CI:1.41–1.74, p < 0.001) [28]. Among the four subtypes of invasive ductal carcinoma patients who achieved pathological complete response (pCR) after neoadjuvant chemotherapy, the HR + /HER-2- group had the highest proportion of N2 + N3, reaching 11.2%. Patients with the HR + /HER-2 subtype exhibited higher N staging and lower lymph node response rates to neoadjuvant chemotherapy, which may also be related to the observed lower overcomes.
Surgery approach is also an independent risk factor for OS and CSS. According to univariate analysis, comparing with breast-conserving surgery, total mastectomy had a worse OS(HR = 1.44, CI:1.17–1.78) and CSS (HR = 1.81, CI:1.42–2.31, p < 0.05). Yu-Chun Song et al. conducted a retrospective analysis of data from 730 patients who underwent neoadjuvant chemotherapy between 2000 and 2014, finding that patients in both the total mastectomy and breast-conserving surgery groups had similar 5-year rates of locoregional recurrence (LRR), distant metastases (DM), and disease-free survival (DFS). However, the breast-conserving surgery group had a significantly higher 5-year breast CSS (98.9% vs. 90.4%, p = 0.005) and OS (98.9% vs. 90.1%, P = 0.003) rates [29]. It is well-known that breast cancer patients undergoing mastectomy often present with larger tumors and a higher frequency of lymph node metastases compared to those who opt for breast-conserving surgery. To balance the baseline differences in factors other than the surgical method among breast cancer patients, Sungchan Gwark et al. utilized propensity score matching to evaluate 1641 patients undergoing neoadjuvant chemotherapy. Their findings indicated that breast-conserving surgery combined with radiotherapy leads to superior disease-free survival (DFS, p < 0.05), distant metastasis-free survival (DMFS, p < 0.05), and overall survival (OS, p < 0.05) in comparison to mastectomy [30]. Combining the results of this study with the latest related research, we found that choosing breast-conserving surgery after neoadjuvant chemotherapy offers better benefits in survival prognosis for patients.
This study has certain limitations. It is a database-based retrospective analysis, and the conclusions may be subject to potential unknown biases or confounding factors. There is a lack of data on the application of HER-2 + targeted drugs and endocrine therapy for HR + patients. Additionally, the SEER database has a short record time for neoadjuvant chemotherapy, lacking longer follow-up data. Moreover, there is a lack of external data validation and data on Disease-Free Survival (DFS) and Local Recurrence Rate (LRR), and this may have also affected the results of our systemic treatment analysis.
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