Recent randomized trial data suggest that the role of primary site surgery in the management of patients with metastatic breast cancer is limited to local control in select cases, with no clear evidence of impact on overall survival rates [9, 10, 11]. However, how to best select these patients who might garner some benefit from primary site surgery remains unknown, with these decisions being made on an individualized basis in clinical practice [13]. Given the known differences between lobular and ductal tumors in regard to surgical management in the early stage setting and disease patterns in the metastatic setting, we explored whether the use of primary site surgery differs in HR-positive HER2-negative metastatic lobular versus ductal breast cancer.
In this cohort of 25,294 patients from the National Cancer Database, we found both similarities and differences in the management of metastatic HR-positive HER2-negative breast cancer by histologic subtype. First, despite the lack of definitive data demonstrating a survival benefit from primary site surgery, a significant proportion of patients overall underwent primary site surgery (28.3%). While primary site surgery was more commonly utilized in those with bone-only metastases, and those with ILC were more likely to have such a disease pattern, the overall usage of primary site surgery in the ILC cohort was slightly but significantly lower than in the IDC cohort. Although a slightly smaller proportion of patients with ILC had primary site surgery, the majority of factors associated with receiving surgery did not differ between the lobular and ductal groups; in both groups, primary site surgery was more common among younger patients, those with T2 or T3 tumors, those with more nodal disease, and those with private insurance.
Interestingly, while patients with ILC had larger tumors than those with IDC, there was no difference in the rate of mastectomy by histologic subtype amongst those who had primary site surgery. This differs from the early-stage setting, where lobular histology is associated with higher mastectomy rates. Similar to the early-stage setting, however, those with metastatic ILC who had primary site surgery experienced significantly higher positive margin rates than those with metastatic IDC. This raises the possibility that the local control benefit of primary site surgery might be attenuated in those with ILC, who may require more extensive surgery to achieve negative margins. We did find an association between local radiotherapy and improved overall survival in this cohort; whether this association reflects a relationship between improved local control and survival outcomes versus improved outcomes in those selected to have radiation is unknown. Of note, patients with ILC were significantly less likely to receive radiation than those with IDC, which is consistent with other studies [16, 17].
One interesting finding regarding management of the primary tumor in this metastatic cohort is the significantly lower odds of primary site surgery in patients with T4 tumors in both lobular and ductal groups. Since the most accepted purpose of primary site surgery in the stage IV setting is for palliation, we would have expected higher rates of surgery in those with T4 tumors. Alternatively, these tumors may have been deemed unresectable; one of the challenges of analyzing this retrospective dataset is the inability to discern the reasons for performing primary site surgery.
This limitation likely impacts the strong association between primary site surgery and improved OS that we found in both ILC and IDC patients. For example, we found that in both the ILC and IDC cohorts, patients who had private insurance were more likely to have surgery compared to patients who had public insurance. The improved outcomes associated with primary site surgery may reflect improved access to care as opposed to a biologic effect of surgery. While we attempted to adjust for potential confounders in the propensity score matched model, we are likely unable to account for the many factors that influence why surgery would be used in some patients versus others.
Of more interest, perhaps, is the finding that the use of pre-operative systemic therapy was associated with improved OS in the IDC cohort, but not in the ILC cohort. We suspect that pre-operative systemic therapy in the IDC cohort may have helped to select patients who would have more durable response to therapy, and therefore have improved OS. In contrast, response to therapy in those with ILC may be more difficult to ascertain, or less likely to be associated with outcomes.
For systemic therapy, those with ILC were significantly more likely to receive endocrine therapy than those with IDC, despite all studied cases being HR-positive. Likewise, those with IDC were more likely to receive chemotherapy. This treatment pattern has been observed in previous literature and may point to the notion that early-stage ILC has reduced sensitivity to chemotherapies, or perceived as such, and therefore utilized less frequently [18, 19]. However, more recent studies show that in the metastatic setting, response to eribulin and CDK4/6 inhibitors may be similar between ILC and IDC [20, 21]. These findings highlight the need to identify lobular specific therapies for those with metastatic disease.
As a secondary endpoint, we also looked at OS by histology. Similar to our findings, worse OS in those with metastatic ILC has been shown in other studies as well [2, 3, 22]. While the underlying reason for this difference is unclear, it suggests that ILC is indeed biologically different than IDC, given differential outcomes despite restricting the study population to those with HR-positive, HER2-negative tumor types, and ILC tumors being of lower grade than IDC tumors. One potential explanation could be that those with metastatic ILC may have an overall higher burden of disease than is typically detected on standard imaging modalities [23]. For example, studies comparing fluorodeoxyglucose positron emission tomography (FDG-PET) to 18F-fluoroestradiol positron emission tomography (FES-PET) show that some metastatic lesions in ILC appear only on FES-PET [24, 25].
To our knowledge, this is the largest reported study evaluating primary site surgery by histologic subtype in the setting of metastatic breast cancer. However, this study is subject to a number of limitations, including selection bias, lack of detailed systemic therapy information, lack of specific radiation field data, and the absence of local recurrence events as an endpoint. However, the findings reflect real-world management patterns which appear to differ by histologic subtype.
While ILC has long been regarded as a less aggressive tumor type, our findings from this large NCDB study are consistent with others showing worse outcomes in ILC than IDC. While the differences between the IDC and ILC groups in this study were relatively small, it is interestingly to note that histology appears to be influencing management among this HR-positive HER2-negative group of patients with stage IV breast cancer. The use of primary site surgery was slightly lower, and the use of both radiotherapy and chemotherapy were much lower in those with metastatic ILC compared to metastatic IDC. Coupled with shorter overall survival in the ILC cohort, these findings reinforce the need for histologic subtype-specific management options. In regard to surgical management, the significantly larger tumor size and higher positive margin rates in the ILC cohort suggest that if primary site surgery is to be utilized, one should consider a larger excision and likely incorporate radiotherapy to maximize potential benefit of locoregional intervention. Whether such outcomes reflect under-staging, and the need to better identify disease extent in ILC, or lack of ILC specific treatments is unknown. Regardless, further work is needed to improve management outcomes for those with metastatic ILC.