Impact of histology subtypes (ductal, lobular, and mixed ductal/lobular) on pathological complete response (pCR) following neoadjuvant chemotherapy (NAC) and chemoimmunotherapy (NACI) for estrogen receptor low (ER-low) HER2-negative breast cancer

Background: Little is known regarding mixed ductal/lobular histology subtypes of breast cancer in terms of how they influence the likelihood of pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) & chemoimmunotherapy (NACI). Similarly, there is no literature on how estrogen receptor (ER) expression percentiles influence the likelihood of pCR after NACI among this mixed histology subgroup. Methods: We examined data within the National Cancer Database on those diagnosed with HER2-negative breast cancer between 2018-2022. We categorized patients based on histology subtype (ductal, lobular, & mixed) and ER percentiles, including ER-low (1-10%). Binary logistic regression was used to examine the relationship between pCR & histology type among patients with ER-low disease, adjusting for age, race, ethnicity, tumor grade, tumor size, nodal status, progesterone receptor percentiles, immunotherapy use, endocrine therapy use, & lymphovascular invasion (LVI). Additionally, adjusted Cox proportional hazards regression was fitted between overall survival (OS) and histology subtype. Results: A total of 58072 ductal, 1330 mixed, & 3500 lobular cases with available residual disease data following neoadjuvant therapy were examined. Among those with ER-low expression (ductal: 3319, mixed: 35, lobular: 80), it was shown that 46.7% (n=1549), 31.4% (n=11), & 12.5% (n=10) of patients, respectively, achieved pCR, which was a significant difference on univariate analysis (p<0.001). On adjusted analysis, the difference in pCR between patients with mixed & ductal ER-low disease was non-significant (aOR 0.69, 95%CI 0.27-1.77, reference: ductal). However, lobular patients were associated with 79% lower odds of achieving pCR compared to ductal patients (aOR 0.21, 95%CI 0.08-0.54). On multivariate analysis, variables that significantly improved the odds of achieving pCR were histology type (p=0.004), younger age (p=0.010), smaller tumor size (p<0.001), use of immunotherapy (p<0.001), and absence of LVI (p<0.001). For OS, larger tumor size (p<0.001), positive nodal status (p<0.001), & presence of LVI (p<0.001) were associated with worsened OS whereas the receipt of endocrine therapy (p=0.003) significantly improved OS. Histology subtype was not significantly associated with differences in OS (p=0.238). Conclusion: Tumors of mixed ductal/lobular histology behave more similarly to ductal disease in terms of NACI response, including ER-low subgroups. Additional factors, such as tumor size, LVI, and receipt of immunotherapy play a stronger role in predicting pCR, but the histology subtype remains an important variable to consider when deciding how best to sequence treatment for those with HER2-negative ER-expressing disease.