HER2-enriched tumor initiating cell (HTIC) genomic predictor of response following neoadjuvant trastuzumab-based chemotherapy in HER2+ breast cancer
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ABSTRACT: We identified a 17-gene Her2-enriched tumor initiating cell (HTIC) signature in MMTV-Her2/Neu mouse mammary TICs. Here, we show that patients with HTICS+ HER2+:ERα− tumors are more likely to achieve a pathologic complete response to trastuzumab-based neoadjuvant chemotherapy compared with HER2+:ER+ tumors. Neoadjuvant study of 50 HER2-positive breast cancer cases treated with trastuzumab-based chemotherapy pre-operatively. Pre-treatment FNA from primary tumors were obtained and RNA extracted and hybridized to Affymetrix microarrays according to manufacturer protocol. Pathologic response was assessed at the end of neoadjuvant treatment.
Project description:We identified a 17-gene Her2-enriched tumor initiating cell (HTIC) signature in MMTV-Her2/Neu mouse mammary TICs. Here, we show that patients with HTICS+ HER2+:ERα− tumors are more likely to achieve a pathologic complete response to trastuzumab-based neoadjuvant chemotherapy compared with HER2+:ER+ tumors.
Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients do not benefit from this treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. The series comprised 24 incisional biopsies of breast carcinomas derived from patients that received neoadjuvant trastuzumab based therapy. Gene expression profiling was performed using RNA from frozen core biopsies from 24 patients with primary HER2-positive (HER2+) tumors treated with neoadjuvant chemotherapy and trastuzumab.
Project description:Adjuvant docetaxel, carboplatin, and trastuzumab (TCH) is a standard regimen for HER2+ breast cancer. Dual HER2-blockade with lapatinib (L) and trastuzumab demonstrated significant activity in the metastatic and neoadjuvant settings. This study evaluates neoadjuvant TC plus trastuzumab (H) and/or lapatinib (L). This study demonstrated a similar pCR rate with TCH and TCHL and a lower rate of pCR with TCL. Treatment-related toxicity limited the ability for participants to receive protocol-specified chemotherapy and HER2-targeted therapy in the TCHL Arm.
Project description:Adjuvant docetaxel, carboplatin, and trastuzumab (TCH) is a standard regimen for HER2+ breast cancer. Dual HER2-blockade with lapatinib (L) and trastuzumab demonstrated significant activity in the metastatic and neoadjuvant settings. This study evaluates neoadjuvant TC plus trastuzumab (H) and/or lapatinib (L). This study demonstrated a similar pCR rate with TCH and TCHL and a lower rate of pCR with TCL. Treatment-related toxicity limited the ability for participants to receive protocol-specified chemotherapy and HER2-targeted therapy in the TCHL Arm.
Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients do not benefit from this treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. The series comprised 24 incisional biopsies of breast carcinomas derived from patients that received neoadjuvant trastuzumab based therapy.
Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients do not benefit from this treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. The series comprised 18 incisional biopsies of breast carcinomas derived from patients that received neoadjuvant trastuzumab based therapy.
Project description:Ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel plus trastuzumab and pertuzumab (THP) are two of the experimental regiments evaluated in I-SPY 2, a neoadjuvant platform trial for high risk, early stage breast cancer. In pre-defined analyses we assessed 10 biomarkers at the pre-treatment timepoint in the HER2, ER/PR, and proliferation pathways to test their association with pCR (complete pathologic response).
Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients relapse after treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. To search for genes predictive of relapse in HER2-positive breast carcinoma patients treated with adjuvant trastuzumab, we conducted gene expression profiling analysis in 53 cases treated in the clinic with doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF) and trastuzumab. Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded tissues from 53 patients with primary HER2-positive (HER2+) tumors. The series consists in 23 relapsed and 30 non-relapsed cases with similar clinical-pathological characteristics (size, pathological lymph node involvement and estrogen receptor positivity) (3-year median follow up).
Project description:The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate as compared to chemotherapy plus either trastuzumab or lapatinib. An extensive biomarker programme was prospectively planned to identify potential predictors of sensitivity to different treatments and evaluate treatment effect on tumor biomarkers. A mutation in PIK3CA exon 20 or 9 was documented in 20% of the cases. Overall, the pCR rates were similar in PIK3CA wild type and PIK3CA mutated patients (33.3% vs 22.7%; p=0.323). However, for patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild type tumors (48.4% vs 12.5%; p=0.06). Ki67, pAKT and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. In conclusion, PIK3CA mutations seem to identify patients less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of PI3K pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib.
Project description:The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate as compared to chemotherapy plus either trastuzumab or lapatinib. An extensive biomarker programme was prospectively planned to identify potential predictors of sensitivity to different treatments and evaluate treatment effect on tumor biomarkers. A mutation in PIK3CA exon 20 or 9 was documented in 20% of the cases. Overall, the pCR rates were similar in PIK3CA wild type and PIK3CA mutated patients (33.3% vs 22.7%; p=0.323). However, for patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild type tumors (48.4% vs 12.5%; p=0.06). Ki67, pAKT and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. In conclusion, PIK3CA mutations seem to identify patients less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of PI3K pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib.