Her2+ and Hormonal Therapy

In BC literature, there has been much discussion of "tamoxifen resistance" in Her2+ breast cancer.  Basically what this means is that in pre-Herceptin days, Her2+ Hormone Receptor (HR) + women don't do as well as Her2- HR+ women and that tamoxifen did not help prevent relapse in Her2+ women as much as for Her2- women.

So.... there has been a trend in the last few years, ever since the big aromatase inhibitor trials were published, to give Her2+ ER+ women an AI instead of tamoxifen.  However, as far as I know, the big AI studies did not look at Her2 status or CYP metabolizer status separately.  They grouped all women together and concluded that AIs are better than tamoxifen.  The big TEAM trial (Tamoxifen and Exemestan Adjuvant Multinational) trial was one of the trials that showed that AI was superior to tamoxifen.

Looking back, based on determining HER status of 4308 stored tumor blocks from this trial, they found that 1275 were Her+, and that exemestane (an AI) did not provide benefit over tamoxifen for Her2+ women (or for low risk women either).  This is a very large study, thus the data are very strongly statistically significant (not likely due to chance.)

However, despite the controversy around CYP2D6 testing, it would still give me the heebie jeebies to be on tamoxifen if I were a poor or intermediate metabolizer of tamox.

Also, despite "tamoxifen resistance" it is highly likely that hormonal treatment does provide some benefit - in both Herceptin studies HERA and Study No N9831, HR+ had fewer recurrences than HR negative (result was statistically significant).

 From SABCS 2009:

[75] The TEAM Trial Pathology Study Identifies Potential Prognostic and Predictive Biomarker Models for Postmenopausal Patients Treated with Endocrine Therapy.

Bartlett JMS, Brookes C, Robson T, van de Velde CH, Billingham LJ, Campbell FM, Quintayo M-A, Lyttle N, Hasenburg A, Hille ETM, Kieback D, Putter H, Markopoulos C, Meershoek-Klein-Kranenbarg E, Paridaens R, Seynaeve C, Mallon EA, Rea DW University of Edinburgh, Edinburgh, United Kingdom; University of Birmingham, Birmingham, United Kingdom; Leiden University Medical Centre, Leiden, The Netherlands; University Hospital, Freiburg, Germany; Diako Hospital, Bremen, Germany; Athens University Medical School, Athens, Greece; Western Infirmary Glasgow, Glasgow, United Kingdom; UZ Gasthuisberg, Leuven, Belgium; Erasmus MC-Daniel-den Hoed Cancer Centre, Rotterdam, The Netherlands

Background: The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included prospectively planned biomarker studies to identify prognostic and predictive biomarkers for patients receiving endocrine therapy. Quantitative IHC data for ER/PgR (Can Res 69:83S, SABCS2008), HER2, HER3 and Ki67 was available for the current analysis relative to outcome of estrogen receptor-positive (ER+) early postmenopausal breast cancer (BC) patients treated with exemestane versus tamoxifen.
Patients & Methods: Pathology blocks from 4598 TEAM patients were collected and tissue microarrays constructed. Quantitative analysis of hormone receptors (HER2/3) by conventional IHC, and image analysis derived continuous scores for Ki67/ER/PgR were analyzed relative to disease-free survival and treatment on an intent to treat basis using survival data for the first 2.75 years of the TEAM trial. Data on HER2FISH and EGF Receptor IHC will be presented.
Results: Of 4595 eligible cases samples received, 16 were excluded, 271 had incomplete biomarker data, leaving 4308 patients for the final biomarker analysis. 1275 (30%) cases were HER2/3 positive.
A significant treatment by marker effect was observed for exemestane versus tamoxifen with HER2/3 negative casesderiving benefit from aromatase inhibitor treatment (HER2/3-ve HR=0.69 95%CI, 0.53-0.88; HER2/3 pos HR, 1.13; 95%CI, 0.82-1.55; p=0.016 for interaction in multivariate analysis). By conventional and STEPP analysis no predictive effect of Ki67 was observed. In multivariate regression analysis increased HER2 expression (P=0.0001) decreased PgR expression (P<0.0001) and increased percentage of Ki67 positive cells (P=0.004) as continuous IHC variables were independently prognostic as were size (P=0.0001), nodal status (P<0.0001), grade (P=0.03) and age (P<0.0001).
Conclusion: Multiple biological parameters (HER2/PgR/Ki67) are independently prognostic in ER+ve early postmenopausal BC. Modelling will be explored to derive prognostic and potentially predictive biomarker signatures for application in BC. Preferential exemestane versus tamoxifen treatment benefit was seen in HER2/3 negative cases, whilst HER2/3 positive cases had a poor prognosis in this population receiving hormonal therapy (suggesting resistance to endocrine therapy), and no evidence of benefit from AIs versus tamoxifen. Type I receptor tyrosine kinases may identify breast cancers with relative resistance to all forms of endocrine therapy. Whilst Ki67 alone was not predictive of benefit from Ais, Ki67, HER2 and PgR were independent prognostic variables and modelling of predictive/prognostic effects may further inform treatment selection in early postmenopausal breast cancer.

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Disclosure:  I do not want to go on an AI, and am looking for evidence to support my choice, just so my onc doesn't think I'm loopy.