Background: Patients with clinically HER2−positive (clinHer2+) tumors often receive trastuzumab in combination with chemotherapy as their standard of care. This study sought to determine the predictive value of the HER2−enriched (HER2−E) molecular subtype for sensitivity to neoadjuvant anthracycline/taxane containing chemotherapy and a trastuzumab plus taxane-based regimen within clinHer2+ disease.
Materials and methods: Gene expression data on pre-treatment fresh-frozen tumor tissues were collected from a combined cohort of MDACC/I-SPY trial (GSE25055/65), and the XeNA trial (GSE22358). Patients from MDACC/I-SPY were treated with doxorubicin/cyclophosphamide (AC) or 5-fluorouracil/epirubicin or doxorubicin/C (FEC or FAC) sequentially with paclitaxel. All patients from XeNA received capecitabine/docetaxel (and trastuzumab if clinHer2+). Intrinsic subtypes were determined using PAM50. Chisquare test and multivariable logistic regression analysis were used to test significance of association between subtype and pathological complete response (pCR or residual cancer burden [RCB] 0/1) and residual disease (RD or RCB2/3) adjusted with pre-treatment tumor size. Kaplan Meier was used for distant relapse-free survival (DRFS) estimates.
Results: For the MDACC/I-SPY cohort (n=595), pCR rates for intrinsic subtypes were 3% (5/168) for LumA, 16% (14/90) for LumB, 33% (23/69) for HER2−E and 37% (76/208) for Basal-like. Tumors achieving RCB0/1 were significantly associated with better DFRS compared to those tumors with RCB 2/3, even within each intrinsic subtype. The 5-year DFRS for HER2−E with RCB0/1 and RCB2/3 was 100% and 31% (p=0.007), respectively. ClinHer2+ status was also significantly associated with pCR (34% vs. 19%, p=0.016). Strikingly, among the clinHer2+ tumors (n=47), 75% (12/16) of the responders were classified as HER2−E (Table 1A) and those tumors that were clinHer2+/HER2−E had 6 times odds to achieve pCR when compared to clinHer2+/non-HER2−E. In the XeNA trial (n=122), the HER2−E subtype was significantly associated with response, composing 85% (7/8) of the clinHer2+ who achieved a pCR. Finally, clinHer2+/HER2−E tumors were 34 times more likely to achieve pCR than clinHer2+/non-HER2−E tumors (Table1B).
Conclusion: The sensitivity of clinHer2+ tumors to neoadjuvant anthracycline/taxane-based regimens, and trastuzumab-based chemotherapy is mainly contained within tumors of the HER2−E subtype. Given that this molecular subtype cannot simply be recapitulated using clinical ER and HER2 status, our results highlight the importance of identifying patients with HER2−E tumors as this appears to greatly enrich for responsiveness and treatment benefit.