This must be a VERY popular topic for research right now - here is another paper than is analyzing response to Herceptin. The study was twofold, looking for response to Herceptin based on a protien (mRNA) for Her2+ and a subset analysis based on ER positivity:
HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer
http://breast-cancer-research.com/co...df/bcr3384.pdf
Of interest, beginning at page 10:
Our investigation shows that in hormone receptor-positive tumors the response to neoadjuvant treatment with trastuzumab plus anthracyline-taxane chemotherapy is driven by the degree of HER2 mRNA expression. This phenomenon could not be observed in the hormone receptor negative subset. Interestingly, Soon Paik’s group has described a similar finding in the adjuvant setting. While their full paper is not published yet, a summary of their results has been included in the recent St. Gallen recommendations: "An interesting STEPP analysis from the adjuvant trastuzumab NSABP B-31 trial examined the degree of HER2 mRNA expression and corresponding trastuzumab benefit separately for patients with estrogen receptor-positive and estrogen receptor-negative disease. The striking finding was that among patients with estrogen receptor-positive disease, trastuzumab benefit in terms of 8-year disease-free survival was entirely confined to those with the higher levels of HER2 mRNA expression."
Similar to these findings in the adjuvant setting, there is a considerable difference in our neoadjuvant study between ESR1pos/HER2pos and ESR1neg/HER2pos tumors. For ESR1neg/HER2pos tumors the amount of HER2 mRNA is not further relevant for response once a tumor is in the HER2-positive group. mRNA levels of HER2 have a dichotomous distribution and HER2can be used as a categorical parameter in this group.
For ESR1pos/HER2pos tumors the situation is different: HER2 mRNA has a more continuous distribution and the response to neoadjuvant trastuzumab/chemotherapy rises continuously with the amount of HER2 mRNA within the HER2-positive tumor group. This suggests that those luminal tumors with a higher activity of the HER2 pathway (measured as increased mRNA levels) are more dependent on this pathway and thus more responsive to trastuzumab targeted therapy. This finding is supported by the STEPP analysis and we observe the same effect with the classical approach of logistic regression, which also shows a significant effect of HER2 mRNA levels (measured as a continuous variable) on pCR only in the ESR1pos/HER2pos group. The traditional method of HER2 SISH ratio or copy number was not able to provide a similar result by STEPP or logistic regression, similar to the finding in the adjuvant HERA trial.
The relevance of a crosstalk between the estrogen receptor pathway and the HER2 pathway has been described in several in vitro cell culture and animal models, AIB-1 as well as PAX2 have been identified as relevant mediators of this crosstalk.The hypothesis derived from those investigations and our results would be that two important growth factor pathways significantly influence ESR1pos/HER2pos tumors and either HER2 or ER may be the driver of cell proliferation and survival. With sustained HER2 inhibition ER could function as a key escape or survival pathway, which may result in resistance to trastuzumab. However when HER2 mRNA expression is very high the primary driver of proliferation may still be the HER2 pathway even in the presence of the activated ER pathway. These findings are consistent with two neoadjuvant trials where a significantly lower pCR rates were observed in ERpos/HERpos tumors compared to ERneg/HER2pos disease. However in a recently reported neoadjuvant trial response rates to anti-HER2 treatment with lapatinib and trastuzumab (without chemotherapy) were fairly high (pCR 21%) when combined with endocrine treatment if hormone receptors were present. As in the adjuvant setting trastuzumab or lapatinib therapy (in contrast to the neoadjuvant approach) is usually combined with endocrine therapy in the HR-positive group, the combined inhibition of both pathways is already clinical practice. It would be interesting to further evaluate the contribution of the endocrine therapy to outcome in ESR1pos/Her2pos tumors.
Hopeful