Comprehensive assessment of cancer stem cell like cells in prediction of pathologic complete response to preoperative dual anti–HER2 therapy for HER2–positive primary breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12123-e12123
Author(s):  
Jose Rodrigo Espinosa Fernandez ◽  
Teruo Yamauchi ◽  
Chiyo K. Imamura ◽  
Hideko Yamauchi ◽  
Hiromitsu Jinno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Tumor Cells ◽  
Prospective Trial ◽  
Pathologic Complete Response ◽  
Predictive Biomarkers ◽  
Preoperative Therapy ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
The Impact

e12123 Background: Chemotherapy for breast cancer destroys non–stem cells while sparing cancer stem cells (CSCs). In contrast, anti–HER2 therapy may eliminate resistant cells because HER2 may be a key driver of CSCs. CSC biomarkers have been found to be prognostic of poor outcome and predictive of resistance to therapy. However, there are no comprehensive studies of the impact of anti-HER2 therapies on CSC–related biomarkers. We conducted a prospective biomarker determination study of breast CSCs characterized by CD44v expression and increased aldehyde dehydrogenase 1 (ALDH1) enzymatic activity or expression. Methods: In a prospective trial (ClinicalTrials.gov: NCT01688609), 18 patients with operable primary HER2+ breast cancer (≥T2 excluding inflammatory, any N; median age of 54 yrs) were treated with preoperative anti–HER2 therapy following the NeoALTTO trial dual therapy arm regimen, with a goal of identifying novel predictive biomarkers for pCR. Proportions of tumor cells with CSC characteristics, defined as CD44v+ and ALDH1+, were estimated at baseline, at 6 weeks (after therapy with lapatinib/trastuzumab) and at 18 weeks (after therapy with lapatinib/trastuzumab and paclitaxel) to assess adaptive response. We determined changes in the quantity and characteristics of CSC–related biomarkers during preoperative therapy and correlated them to tumor response. Results: Out of 18 patients, 8 (44%) had a pCR; 5 of these 8 patients (62%) were positive for CD44v staining on tumor cells at baseline and none were positive on the 6–week biopsy. In contrast, 6 of the 10 patients without pCR exhibited persistent levels, or enrichment of CD44v proportion and expression at 6 and 18 weeks (p = 0.0128). ALDH1 expression and other biomarkers were not statistically significant predictors of pCR. Conclusions: Enrichment of CD44v+ tumor cells after double anti–HER2 therapy may predict poor response to dual anti–HER2 therapy with cytotoxic chemotherapy. A second biopsy after the start of preoperative therapy may reflect biological changes useful for the guidance and application of therapeutic strategies for patients with HER2+ breast cancer. Clinical trial information: NCT01688609.

Drug Development: Neoadjuvant Opportunities in Breast Cancer

2013 ◽  
pp. 73-79
Author(s):  
Priya Rastogi ◽  
Charles E. Geyer ◽  
Eleftherios P. Mamounas ◽  
Angela DeMichele
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Cancer Biology ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Predictive Biomarkers ◽  
Preoperative Therapy ◽  
New Agents ◽  
Her2 Breast Cancer ◽  
Improved Outcomes

Preoperative therapy allows for a higher rate of breast conserving surgery and has been shown equivalent to adjuvant therapy. Preoperative therapy provides an opportunity to obtain insights into breast cancer biology and to accelerate the evaluation of new therapies. Clinical trials have shown that women who achieve a pathologic complete response (pCR) have substantially improved outcomes compared with those who do not achieve a pCR. The U.S. Food and Drug Administration (FDA) meta-analysis demonstrated that the association of pCR and long-term outcomes is greater in women with aggressive breast cancer subtypes. In patients with HER2+ breast cancer, the addition of trastuzumab to chemotherapy in the neoadjuvant setting has doubled pCR and correlated with improved outcomes. Clinical trials will evaluate tailoring the use of radiation therapy in patients who have received neoadjuvant therapy. Trials have established neoadjuvant endocrine therapy as a valid treatment and research option for ER-rich breast cancer. The neoadjuvant setting allows for evaluation of endocrine therapies in combination with newer targeted therapies in the appropriate patient populations. The neoadjuvant setting provides opportunity to accelerate the evaluation of new agents, improve pCR rates, and identify predictive biomarkers for response. This setting provides the opportunity for screening new agents in combination with chemotherapy while obtaining serial biopsies to understand biology of response and resistance. Although current standard therapies provide substantial benefits for patients with a pCR, patients with residual disease are at substantial risk for disease recurrence. New agents are being evaluated in patients with high-risk residual disease following standard treatment regimens.

Correlation of quantitative p95HER2, HER2, and HER3 protein expression with pathologic complete response (pCR) in HER2-positive breast cancer patients (pts) treated with neoadjuvant chemotherapy and trastuzumab.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 137-137 ◽  
Author(s):  
Jose Caetano Villasboas ◽  
Judith Hurley ◽  
Jodi Marie Weidler ◽  
Agnes Paquet ◽  
Carmen Gomez Fernandez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pathologic Complete Response ◽  
Metastatic Breast ◽  
Complete Response ◽  
Invasive Disease ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Additional Information ◽  
Her2 Breast Cancer ◽  
Poor Outcomes

137 Background: Elevated p95HER2 [HER2-M611-CTF (carboxy-terminal-fragment) also known as p95] expression has been correlated with poor outcomes in HER2+ pts with metastatic breast cancer treated with trastuzumab (T); however, limited data is available on the correlation between p95 and pCR to T in the neoadjuvant (NEO) setting, where p95 was measured by immunohistochemistry. The current study aims to determine whether quantitative p95, HER3 and HER2 expression correlated with pCR in pts treated with T + chemotherapy in the NEO setting. Methods: pCR data and quantitative HER2 (H2T), p95, and HER3 (H3T) results by HERmark/VeraTag assays were available in 45 patient cases with pre-therapy, formalin-fixed, paraffin-embedded breast tumors. pCR was defined as the absence of invasive disease in the breast. Quantitative biomarker data were correlated with pCR according to previously published or presented biomarker cutoffs. Results: The overall pCR rate was 46.7% (ER+: 14.3% vs. ER-: 75%; p<0.0001) and was significantly associated with higher H2T levels (p=0.02) and lower H3T levels (p=0.04). In ER- subjects (N=24), no difference in H2T levels was observed between pCR vs non-pCR groups (median H2T=111.5 vs 150.5, respectively; p=0.721). However, within the ER+ group (N=21), H2T levels were significantly higher in the pCR group vs non-pCR group (median H2T=254 vs 37.3; p=0.024). Using multivariate logistic regression, increasing log(H2T) (p = 0.012), ER-negativity (p = 0.027) and low p95 (p = 0.074) were found to correlate or trend with pCR. Conclusions: pCR was significantly associated with high H2T, particularly in ER+ HER2+ breast cancer pts who received NEO therapy with T + chemotherapy. Lower H3T was also associated with pCR. A trend towards pCR was seen in tumors with low p95. These data suggest that quantitative H2T, H3T and p95 may provide additional information on response to T-based regimens in breast cancer stratified by ER status. Additional investigation into the relationship between quantitative H2T, p95 and H3T expression and T response in the NEO setting in larger cohorts is warranted.

Neoadjuvant and Adjuvant Therapy for HER2 Positive Disease

2015 ◽  
pp. e41-e48 ◽  
Author(s):  
Stephen K. Chia
Keyword(s):  
Breast Cancer ◽  
Pathologic Complete Response ◽  
Predictive Biomarkers ◽  
Complete Response ◽  
Her2 Positive ◽  
Poor Prognostic Factor ◽  
Her Family ◽  
Clinically Significant ◽  
Initial Description ◽  
American Society

Since the initial description of the HER2 proto-oncogene as a poor prognostic factor in breast cancer in 1987, to the first randomized trial of a monoclonal antibody directed against HER2 in combination with chemotherapy for the treatment of metastatic HER2-positive breast cancer published in 2001, to the American Society of Clinical Oncology (ASCO) 2005 Annual Meeting in which we saw the unprecedented collective presentations demonstrating the dramatic benefit of trastuzumab in the adjuvant setting—the clinical landscape of HER2-overexpressing breast cancer has forever changed. More recently, there has been increasing use of preoperative chemotherapy and anti-HER2 targeted therapies in primary operable HER2 disease in the research domain and in clinical practice. In the next few years, we will see if dual adjuvant anti-HER2 antibody inhibition produces clinically significant improvements in outcome; understand if there is a role of small molecule inhibitors of the HER family of receptors either in combination or sequential to trastuzumab; further refine the relationship between pathologic complete response (pCR) and long-term clinical outcomes; and find predictive biomarkers to identify cohorts of patients that may need differential combinations and/or durations of anti-HER2 therapies.

Discrepancy of pathologic complete response and outcome between breast tumor and axillary node in HER2 positive breast cancer after neoadjuvant chemotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12503-e12503
Author(s):  
Shin-Cheh Chen ◽  
Hsien-Kun Chang ◽  
Yung-Chang Lin ◽  
Shih Che Shen ◽  
Wen-Lin Kuo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Neoadjuvant Chemotherapy ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Axillary Node ◽  
Her2 Positive ◽  
The Impact ◽  
Better Than ◽  
Positive Breast Cancer

e12503 Background: The pathologic complete response (pCR) rate in primary tumor and axillary node after different chemotherapy regimens of neoadjuvant chemotherapy (NAC) in HER2 positive breast cancer (BC) is unknown, the impact of pCR on disease free survival (DFS) and overall survival (OS) is still controversial. Methods: A cohort of 350 HER2 positive BC (296 cytologically proved axillary node metastasis) received NAC with different regimens, antracyclin with taxotere (AT), docetaxel with transtuzumab (DT) and docetaxel with transtuzumab and pertuzumab( DTP) between 2005 and 2016 in a large medical center were analyzed retrospectively. The impact of pCR rates of breast and axillary node on DFS and OS were analyzed. Results: Of 350 women with HER2 positive BC received NAC, median age was 50 years(18~93), median tumor size was 4.3 cm, the pCR rates of breast and axillary node were 16.2% and 28.7% ( P= 0.018) in patients received AT( n= 130) , 47.6% and 66.9% ( P= 0.00028 ) in patients received DT( n= 191) ,65.5% and 77.8% ( P= 0.372 ) in patients received DTP( n= 29), respectively. The 5-year DFS were 79.3% and 66.0% ( p= 0.0023), 5-year OS were 89.5% and 76.6% ( P= 0.0201) in patients with breast pCR and non-pCR, respectively. The 5-year DFS were 75.7% and 58.4% ( P= 0.00037), 5-year OS were 85.7% and 72.6% ( P= 0.0024) in axillary pCR and non-pCR patients, respectively. The 5-year DFS were 79.3% and 75.7% ( P= 0.430), and 5-year OS were 89.5% and 85.7% ( P= 0.695) in breast and axillary pCR, respectively . The 5-year DFS in breast pCR whom received targeted therapy (DT and DTP groups) was significantly better than whom not received targeted therapy (AT groups), 85.3% and 65.0% ( P= 0.039), respectively Conclusions: Higher pCR rate in axillary node than breast was found in this cohort. Either pCR in axillary node or breast was associated with improved DFS and OS, but no difference of DFS and OS between breast and axillary pCR . The 5-year DFS in breast pCR received targeted therapy were significantly better than breast pCR patients received chemotherapy alone.

scholarly journals PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1566 ◽  
Author(s):  
William P. D. Hendricks ◽  
Natalia Briones ◽  
Rebecca F. Halperin ◽  
Salvatore Facista ◽  
Paul R. Heaton ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Patients ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Expression Signature ◽  
Her2 Breast Cancer ◽  
Group 2

The therapeutic HER2-targeting antibody trastuzumab has been shown to elicit tumor immune response in a subset of HER2-positive (HER2+) breast cancer. We performed genomic and immunohistochemical profiling of tumors from eight patients who have completed multiple rounds of neoadjuvant trastuzumabb to identify predictive biomarkers for trastuzumab-elicited tumor immune responses. Immunohistochemistry showed that all tumors had an activated tumor immune microenvironment positive for nuclear NF-κB/p65RelA, CD4, and CD8 T cell markers, but only four out of eight tumors were positive for the PD-1 immune checkpoint molecule, which is indicative of an exhausted immune environment. Exome sequencing showed no specific driver mutations correlating with PD-1 positivity. Hierarchical clustering of the RNA sequencing data revealed two distinct groups, of which Group 2 represented the PD-1 positive tumors. A gene expression signature that was derived from this clustering composed of 89 genes stratified HER2+ breast cancer patients in the TCGA dataset and it was named PD-1-Associated Gene Expression Signature in HER2+ Breast Cancer (PAGES-HBC). Patients with the Group 2 PAGES-HBC composition had significantly more favorable survival outcomes with mortality reduced by 83% (hazard ratio 0.17; 95% CI, 0.05 to 0.60; p = 0.011). Analysis of three longitudinal samples from a single patient showed that PAGES-HBC might be transiently induced by trastuzumab, independent of clonal tumor expansion over time. We conclude that PAGES-HBC could be further developed as a prognostic predictor of trastuzumab response in HER2+ breast cancer patients and be potentially used as an alternative biomarker for anti-PD-1 therapy trials.

The impact of hormone receptor status on pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy with or without trastuzumab

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 533-533
Author(s):  
F. Peintinger ◽  
A. Buzdar ◽  
H. Kuerer ◽  
A. Gonzalez-Angulo ◽  
C. Hatzis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Hormone Receptor ◽  
Pathologic Complete Response ◽  
Pathologic Response ◽  
Weekly Paclitaxel ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
The Impact ◽  
Positive Breast Cancer

533 Background: The aim of this study was to compare the extent of pathologic response in HER2-positive patients treated with standard neoadjuvant chemotherapy with or without trastuzumab according to hormone receptor (HR) status. Methods: The study included 199 patients with HER2-positive disease treated in clinical trials of neoadjuvant chemotherapy. Eighty-nine patients treated with 3- weekly paclitaxel and concurrent trastuzumab followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) were compared with 110 patients treated with weekly or 3-weekly paclitaxel followed by FEC or FAC. Residual cancer burden (RCB), a measurement of residual disease (RD) from pathologic review of the primary tumor and lymph nodes, was classified as pathologic complete response (pCR), RCB-I (near-pCR, minimal RD), RCB-II (moderate RD), or RCB-III (extensive RD). RCB was compared between treatment groups according to HR status. Results: In HR-negative patients, similar pCR rates were achieved with weekly T/FAC as with 3-weekly T/FEC and trastuzumab (61% and 65%, respectively). However, in HR-positive patients, higher pCR rates were achieved with 3-weekly T/FEC and trastuzumab (47%) than with the weekly T/FAC (25%; p=0.04) or 3-weekly T/FAC (19%; p=0.01) ( Table 1 ). Near pCR (RCB-I) was slightly higher in HR-positive (26%) than in HR-negative patients treated with 3-weekly T/FEC and trastuzumab (11%; p=0.07). Conclusions: Patients with HR- negative/HER2-positive breast cancer had similar pathologic response rates from addition of trastuzumab to 3-weekly T/FEC or from weekly T/FAC chemotherapy. Patients with HR-positive/HER2-positive breast cancer obtained significant benefit from addition of trastuzumab to 3- weekly T/FEC, compared to 3-weekly T/FAC or weekly T/FAC. The combination of weekly T/FEC with trastuzumab as neoadjuvant chemotherapy should be evaluated. [Table: see text] [Table: see text]

Impact of neoadjuvant HER2-directed therapy on HER2 status in breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12130-e12130
Author(s):  
Nicholas Manguso ◽  
Jeffrey Johnson ◽  
Reva Kakkar Basho ◽  
Heather L. McArthur ◽  
Hisashi Tanaka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Therapy ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Residual Tumor ◽  
Her2 Status ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Copy Numbers ◽  
Pre Treatment

e12130 Background: Neoadjuvant chemotherapy (NAC) with HER2-directed therapy has become standard-of-care for most women with potentially curable HER2-positive (HER2+) breast cancer and is associated with a high pathologic complete response (pCR) rate. The HER2 status of residual disease after NAC is not well characterized and could potentially inform clinical decisions about additional systemic therapy. We describe tumoral HER2 status before and after NAC with HER2-directed therapy. Methods: An institutional database was screened to identify patients with stage 1-3 HER2+ breast cancer by fluorescence in situ hybridization (FISH) and/or immunohistochemistry (IHC) who received NAC with HER2-directed therapy followed by resection between 2011 and 2015. Clinicopathologic data was collected. Change in HER2 status by FISH and IHC following treatment was described. Results: 99 patients were identified. Median age was 49 years (range 26-85). Pre-treatment median HER2/CEP17 copy number ratio (CNR) for all tumors was 6.3 (range 1.9-20.7) by FISH and 84 (84.8%) tumors were IHC 3+. 44 (44.4%) patients achieved a pCR. Of the 55 patients with residual disease, 35 had sufficient residual tumor to evaluate HER2 status and 14/35 (40%) were HER2- by FISH and IHC (table). Tumors converting from HER2+ to HER2- had lower pre-treatment median HER2 copy numbers (11.9, range 4.6-22) compared to tumors that remained HER2+ (18.3, range 5.1-48.6; p=0.04) after neoadjuvant therapy. Additionally, pre-treatment median HER2/CEP17 CNR was lower among tumors that converted from HER2+ to HER2- (3.0, range 2.2-8.2) compared to those remaining HER2+ (6.8, range 2-15.7; p=0.02). Conclusions: While pCR rates are high with NAC and HER2-directed therapy, many patients still have residual tumor. In this cohort, 40% of patients with evaluable residual disease after NAC had HER2+ tumors that became HER2-. HER2 conversion was associated with lower pre-treatment HER2 copy numbers and HER2/CEP17 CNR. Conversion from HER2+ to HER2- in patients undergoing neoadjuvant therapy may have clinical significance and biological implications. [Table: see text]

Effect of neoadjuvant pertuzumab-containing regimens on pathologic complete response rates in stage II-III HER2-neu positive breast cancer: A retrospective, single institutional experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 580-580
Author(s):  
Rashmi Krishna Murthy ◽  
Takeo Fujii ◽  
Kenneth R. Hess ◽  
Akshara Singareeka Raghavendra ◽  
Bora Lim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Clinical Stage ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Stage Ii ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Positive Breast Cancer

580 Background: Pertuzumab (P) in combination with trastuzumab (H) based chemotherapy is currently FDA- approved as a standard neoadjuvant treatment for patients with clinical stage II-III HER2-positive (HER2+) breast cancer (BC). The chemotherapy backbone of HER2-targeted therapy varies and may include taxane (T) and/or anthracycline (A), or carboplatin (C). The goal of this study was to retrospectively evaluate the pathologic complete response (pCR) rate for HP-containing regimens compared to H containing regimens for stage II-III HER2+ BC. Methods: We identified all patients (n = 1150) with stage II-III HER2+ BC who received neoadjuvant HER2-targeted therapy from 2005 to 2016 through an institutional database. All patients underwent primary breast and lymph node surgery. pCR was defined as ypT0/is, ypN0. Univariate/multivariate logistic regression and chi-squared test for comparing proportions was used for the statistical analysis. Results: pCR was significantly higher for the HP group (n = 200) compared to the H group (n = 950): 44% vs. 41%, odds ratio = 1.8 (95% CI = 1.3, 2.5; P = 0.0002). Even with adjustment for all clinically significant factors (age, stage, tumor grade, hormone receptor (HR) status, A or C exposure), the improvement was statistically significant (adjusted OR = 2.1 (95% CI = 1.5, 2.9; P < 0.0001). The pCR rate by stage and HR status for the HP group is 62% vs. 55% (stage II vs. III) and 71% vs. 51% (HR- vs. HR+). The effect of P was not modified by HR status (HR-, OR = 2.3; HR+, OR = 1.7, P = 0.39) or by A (A-yes, OR = 1.8; A-no, OR = 2.6) (P = 0.28 for interaction) or C (C-yes, OR 2.6; C-no, OR = 1.8) (P = 0.30 for interaction). P was significantly more likely to be given to patients without A (36% vs. 10%, P < 0.0001) and more likely to be given to patients with C (30% vs. 14%, P < 0.001). In both groups, significant predictors of pCR were found to be stage, HR status, and C exposure. Conclusions: Pertuzumab containing regimens yield higher pCR rates compared to non-Pertuzumab containing regimens in stage II- III HER-2 positive breast cancer. The effect of Pertuzumab is not modified by anthracycline or carboplatin use.

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