Reactive stroma and trastuzumab resistance in HER2-positive early breast cancer.
Amir SonnenblickMali Salmon-DivonRoberto SalgadoEfrat DvashNoam PondéTamar ZahaviAsher SalmonSibylle LoiblCarsten DenkertHeikki JoensuuLieveke AmeyeGert Van den EyndenPirkko-Liisa Kellokumpu-LehtinenAmos AzariaSherene LoiStefan MichielsFrançois RichardChristos SotiriouPublished in: International journal of cancer (2020)
We investigated the value of reactive stroma as a predictor for trastuzumab resistance in patients with early HER2-positive breast cancer receiving adjuvant therapy. The pathological reactive stroma and the mRNA gene signatures that reflect reactive stroma in 209 HER2-positive breast cancer samples from the FinHer adjuvant trial were evaluated. Levels of stromal gene signatures were determined as a continuous parameter, and pathological reactive stromal findings were defined as stromal predominant breast cancer (SPBC; ≥50% stromal) and correlated with distant disease-free survival. Gene signatures associated with reactive stroma in HER2-positive early breast cancer (N = 209) were significantly associated with trastuzumab resistance in estrogen receptor (ER)-negative tumors (hazard ratio [HR] = 1.27 p interaction = 0.014 [DCN], HR = 1.58, p interaction = 0.027 [PLAU], HR = 1.71, p interaction = 0.019 [HER2STROMA, novel HER2 stromal signature]), but not in ER-positive tumors (HR = 0.73 p interaction = 0.47 [DCN], HR = 0.71, p interaction = 0.73 [PLAU], HR = 0.84; p interaction = 0.36 [HER2STROMA]). Pathological evaluation of HER2-positive/ER-negative tumors suggested an association between SPBC and trastuzumab resistance. Reactive stroma did not correlate with tumor-infiltrating lymphocytes (TILs), and the expected benefit from trastuzumab in patients with high levels of TILs was pronounced only in tumors with low stromal reactivity (SPBC <50%). In conclusion, reactive stroma in HER2-positive/ER-negative early breast cancer tumors may predict resistance to adjuvant trastuzumab therapy.
Keyphrases
- early breast cancer
- estrogen receptor
- positive breast cancer
- bone marrow
- epidermal growth factor receptor
- genome wide
- metastatic breast cancer
- early stage
- copy number
- endoplasmic reticulum
- breast cancer cells
- mesenchymal stem cells
- randomized controlled trial
- stem cells
- gene expression
- peripheral blood
- dna methylation
- transcription factor
- phase iii
- binding protein