Public Science Insights: A molecular perspective of clinical benefit: Why shouldn't Luminal-A patients be considered in pCR discussions?

Posted Tue, Jan, 17,2017

Gene expression profiling has led to the molecular classification of breast cancer characterized by intrinsic subtypes: basal-like, HER2-positive, luminal-A, and luminal-B. Although the subtypes are frequently treated as similar entities, there are obvious differences in subtype biological and prognostic characteristics.  These differences are clearly evident in the neoadjuvant setting with pathological complete response (pCR) rates being the surrogate maker of efficacy to a therapeutic regime.  From a clinical perspective, there is a need to understand the value of identifying the intrinsic subtypes, as well as gene expression-based classifications, beyond clinicopathological variables that can identify those patients that would befit from particular therapeutics and the biological mechanisms that explains why subtypes respond to therapies the way they do.

For luminal-A type breast cancers, the most common subtype of all breast cancers, the addition of chemotherapy to endocrine therapy generally provides little benefit. Why is this? One conclusion is that the luminal-A subtype is de novo resistant to some therapies since they are not so sensitive to paclitaxel- and doxorubicin-containing preoperative chemotherapy. Gene expression profiling of luminal-A type cells suggest that Bcl-2 is upregulated in these cells, which indicates that they are perhaps resistant to cytotoxic chemotherapy. Consequently, patients with luminal-A tumors do not derive much benefit from chemotherapy, and pCRs in this subgroup are not very predictive of outcomes. If we were to find a way to sensitize tumor cells to standard chemotherapy will pCR for this subpopulation become predictive? 
Based on meta-analysis the effect by hormone receptor (HR) status is dependent on grade. Patients with grade 1 and 2 who reached pCR still did not do well. Practically, this says that killing all cancer cells in the primary tumor bed does not matter, because patients who had pCR did not do better than those who did not reach pCR. In other words, eradicating all primary tumor cells in ER positive grade 1 and 2 breast cancer is not paralleled with eradication of disseminated tumor cells. This is the challenge. In this case, raising the numbers of pCR for the sake of rising pCR number is unlikely to increase survival. Yet, the fact that pCR rates associated with grade 3 tumors and other tumor subtypes can reflect survival leads to a “what if” one can change grade 1 and grade 2 tumor types to be responsive like grade 3 tumor types.

Reduced sensitivity to various chemotherapeutic drugs is well known to be mediated by high levels of the anti-apoptotic protein Bcl-2 and a low Ki67 expression profile, typical of luminal-A.  If we can overcome Bcl-2 resistance, we can optimize for other breast cancer subtypes. So how do we do this?  One approach is highlighted by considering that Sialic acid-binding lectin (SBL) that displays caspase 3 dependent killing of cancer cells. Selective treatment of cell lines with SBL revealed that SBL induces cell death on estrogen receptor (ER)-positive breast tumors but not on ER-negative breast tumors. The anti-tumor effect of SBL-treated ER-positive breast tumors is accompanied by the down-regulation of ER and Bcl-2. Targeting sialic acid moieties using antibodies that function like SBL or using SBL directly might be additive or synergistic with chemotherapies or with targeted therapies. Sensitizing tumor cells with tumor associated carbohydrate antigens reactive antibodies that facilitates downregulation of Bcl-2 or interrupts survival-signaling pathways to enhance the cytotoxicity of standard chemotherapy would provide a new molecular platform for the development of therapeutic strategies effective against solid tumors and might change treatment paradigms associated with breast cancer. 

Dr Thomas Kieber-Emmons is the author of the recently published paper Relevance of Pathological Complete Response After Neoadjuvant Therapy for Breast Cancer, available for download now in Breast Cancer: Basic and Clinical Research.

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