Abstract P3-07-58: CD44v as a potential predictive biomarker for pathologic complete response in primary HER2+ breast cancer: Utility of adaptive response biopsy in preoperative therapy

2016 ◽  
Author(s):  
T Yamauchi ◽  
CK Imamura ◽  
H Yamauchi ◽  
H Jinno ◽  
M Takahashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adaptive Response ◽  
Pathologic Complete Response ◽  
Predictive Biomarker ◽  
Complete Response ◽  
Preoperative Therapy ◽  
Her2 Breast Cancer

Evaluation of TOP2A and TIMP-1 as predictive markers of pathologic complete response to neoadjuvant anthracycline-based chemotherapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11503-e11503
Author(s):  
Joyce Maria L. Maia ◽  
Elizabeth Santana Santos ◽  
Rafael Costa Lessa ◽  
Felipe D'Almeida Costa ◽  
Stephania Bezerra ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Disease Free Survival ◽  
Predictive Biomarker ◽  
Complete Response ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Her2 Breast Cancer ◽  
Pre Treatment

e11503 Background: Factors predictive of response to anthracyclines can help selecting patients who really benefit from its use. HER2 amplification, TOP2A aberrations, and changes in tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline chemotherapy. Methods: We retrospectively analyzed data on the outcome of patients undergoing neoadjuvant anthracycline-based chemotherapy. Evaluated nuclear TOP2A protein expression and cytoplasmatic TIMP-1 expression in tumor cells in breast cancer biopsies by immunohistochemistry (IHC) and reviewed the pathological responses after completion of neoadjuvant treatment. Results: From 2002 to 2012, data from 97 patients was reviewed. Sixty four patients had the paraffin blocks corresponding to the pre-treatment biopsy to analysis the TOP2A and forty nine to TIMP-1. Patients were considered positive for TOP2A if the level of expression in IHC was higher than 20% and graduated TIMP-1 as weak, moderate or strong expression. Thirty percent of the patients achieved pathologic complete response (pCR) in pos-treatment surgical specimens. There was an association between TOP2A IHC expression and tumor pathological complete response (pCR) with higher pCR in TOPO2A positive tumors (pCR 44% vs 14%; p=0.008). There was no association between TIMP-1 expression and pCR. A moderate or strong TIMP-1 expression was associated with higher disease-free survival in multivariate analysis (p=0,005). No difference in PFS and OS was observed between patients with pCR after a median follow-up of 36 months. Conclusions: The expression of TOP2A seems to be a promising predictive biomarker of pCR to antracycline-based neoadjuvant chemotherapy in HER2 breast cancer. The predictive value and form of assessment of TIMP-1 remain uncertain. These findings should be better evaluated in prospective neoadjuvant trials.

Multi-gene prognostic assays and age-related differences in prediction of pathologic complete response to neoadjuvant chemotherapy and survival in breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 591-591
Author(s):  
Kent Hanson ◽  
Kent Hoskins ◽  
Naomi Yu Ko ◽  
Gregory Sampang Calip
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Neoadjuvant Chemotherapy ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Genomic Testing ◽  
Younger Women ◽  
Her2 Breast Cancer ◽  
Response To Neoadjuvant Chemotherapy ◽  
Overall Mortality

591 Background: Multi-gene testing of primary breast tumors in early-stage breast cancer is used to classify the risk of developing distant metastases and predict the benefit of adjuvant chemotherapy. The association between the tumor genomic prognostic score (GPS) and response to neoadjuvant chemotherapy (NACT) and survival is not well characterized. Our objective was to describe the association between GPS and rates of pathologic complete response (PCR) and subsequent overall survival among women with or without PCR. Methods: We utilized the National Cancer Database to perform a hospital-based, retrospective cohort study of breast cancer patients ages 18 years and older. We included women diagnosed with first primary stages I-III hormone receptor positive (HR+), HER2 negative (HER2-) breast cancer who received NACT and surgery between 2010 and 2017. Women were categorized as having low (0-10 or 200), intermediate (11-25 or 300), or high-risk (25-199 or 400) GPS based on OncotypeDX or MammaPrint scores. Multivariable modified Poisson regression models with robust error variance were used to estimate the crude and adjusted relative risk and 95% confidence intervals (CI) for PCR associated with GPS groups. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) and 95% CI for associations between the GPS and overall survival (OS) in women who did and did not have PCR. Results: A cohort of 3,446 women (mean [SD] age, 56.7 [12.0] years; median [interquartile range] follow-up of 47 [31-68] months) who received genomic testing and neoadjuvant chemotherapy were included in our analysis, of which 935 (27%) were low risk, 1,357 (39%) intermediate risk, and 1,154 (34%) high risk GPS. The relative risk of PCR for all women with high GPS was 1.81 (95% CI, 1.47-2.22; p < 0.001) in crude models and 1.49 (95% CI, 1.16-1.92; p = 0.002) after full adjustment compared to low GPS. Across all models, having a high GPS was significantly associated with achieving PCR in younger women ( < 65 years). In women ages ≥65 years, the association between GPS and PCR was not predictive nor statistically significantly. Among women with no response or partial response to NACT, high GPS was associated with a significantly increased risk of overall mortality (HR 2.41; 95% CI, 1.61-3.60; p < 0.001) compared to low GPS. Conversely, in women who did achieve PCR, GPS was not predictive of overall mortality across all age groups. Conclusions: In women with HR+/HER2- breast cancer, high risk GPS was predictive of PCR following NACT, primarily in younger women ( < 65 years). Our findings also indicated GPS was associated with lower OS in high-risk patients who do not achieve PCR and unpredictive of OS in those without PCR. The utility of tumor genomic testing in the neoadjuvant setting needs further investigation.

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.

Association of NBS1 expression with improved pathologic complete response rate in HER2-overexpressing breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11534-e11534
Author(s):  
Fatma Sen ◽  
Ekrem Yavuz ◽  
Gulcin Yegen ◽  
Hasan Karanlik ◽  
Sitki Tuzlali ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Response Rate ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Protein Loss ◽  
Paraffin Sections ◽  
Her2 Breast Cancer

e11534 Background: Our aim was to investigate potential correlation between expression levels of Nijmegen breakage syndrome1 (NBS1) protein and phosphatidylinositol-3 kinase (PI3K) and pathologic complete response (pCR) rate to neoadjuvant treatment in locally advanced HER2+ breast cancer. We also assess possible association between NBS1 and PI3K expressions. Methods: Totally 42 patients (median age 49 years), received neoadjuvant treatment due to locally advanced HER2+ breast cancer, were included. Immunohistochemical analyses were performed on paraffin sections, obtained during initial diagnosis. Paraffin sections were stained with anti-NBS1 (P95-NBS1 antibody, Y112, ab32074) and anti-PI3K (PI3-Kinase p85 alpha+gamma antibody, ab741369) antibodies to determine positivity of related proteins. Results: NBS1 protein loss was detected in 19 (%45) patients whereas p85 loss was shown in 25 (%60). There was no initial clinicopathologic variable predicting pCR. Fifteen of 30 patients, received neoadjuvant trastuzumab, had pCR, whereas only 1 of 12 patients, not received trastuzumab, achieved pCR (P = 0.012). p85 loss did not predict treatment response, however NBS1 protein expression positively correlated with increased response rate to neoadjuvant treatment (P = 0.007). Conclusions: NBS1 protein expression associates with increased pCR rate in HER2+ breast cancer. However, P85 positivity did not associate with pCR rate or NBS1 overexpression.

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.

Impact of dual anti-HER2 therapy on pathologic complete response rate in breast cancer in a minority-enriched population.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18111-e18111 ◽  
Author(s):  
Jenny Jing Li ◽  
Hsiao Ching Li ◽  
Ang Gao ◽  
Samira K. Syed ◽  
Nisha Unni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Complete Response Rate ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Safety Net ◽  
Her2 Breast Cancer ◽  
Race Ethnicity ◽  
Pathologic Complete Response Rate ◽  
Racial Ethnic

e18111 Background: The addition of pertuzumab (P) to a neoadjuvant trastuzumab (H) plus chemotherapy combination has been shown to significantly improve the pathologic complete response rate (pCR) in localized HER2+ breast cancer; however, minorities have been under-represented in these trials. Racial/ethnic disparities have also been shown to affect outcomes of cancer treatment. This study is aimed to assess the impact of neoadjuvant dual HER2-blockade in an unselected minority-enriched population. Methods: A retrospective chart review was conducted of women with stage I to III HER2+ breast cancer who received neoadjuvant treatment between 2007 and 2017 at an academic institution and its affiliated safety net health system. Data on stage, chemotherapy, race/ethnicity, site of therapy (academic vs safety net hospital), and hormone receptor status were collected. All patients underwent surgery after completion of neoadjuvant chemotherapy. pCR was defined as ypT0/is, ypN0. Chi-squared test and univariate/multivariate logistic regression were used for statistical analysis. Results: The study population included 261 women with the following race/ethnic distribution: 37.7% Non-Hispanic Whites, 34.6% Hispanics, 20.6% Blacks, and 7% other racial/ethnic origin. Ninety-five patients (36%) received chemotherapy-H vs 166 patients (64%) received chemotherapy-HP. Patients at the safety net health system had higher stage at diagnosis compared to the academic site. Site of care and race/ethnicity did not impact the choice of neoadjuvant treatment. The pCR rate was significantly higher for the chemotherapy-HP group (55.4%) compared to the chemotherapy-H group (34.7%) (p = 0.001). There was no association between race/ethnicity, or site of treatment (academic vs safety net), and the probability of achieving pCR. Multivariate analysis showed only dual anti-HER2 therapy (OR: 2.67, CI: 1.55-4.59, p = 0.0004) and hormone-receptor negative status (OR: 2.18, CI: 1.30-3.67, p = 0.0031) to correlate with pCR. Conclusions: Neoadjuvant dual anti-HER2 therapy was more likely to result in a pCR in our minority enriched population. Our data also suggests the combination of chemotherapy-HP confers similar benefit irrespective of race/ethnicity or site of care.

Phase I/II study of neoadjuvant carboplatin, eribulin mesylate, and trastuzumab (ECH) for operable HER2 positive (HER2+) breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS659-TPS659
Author(s):  
Lee Steven Schwartzberg ◽  
Kurt W. Tauer ◽  
Robert C. Hermann ◽  
Petros G. Nikolinakos ◽  
Arthur C. Houts
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Eribulin Mesylate ◽  
Her2 Breast Cancer ◽  
Level 1

TPS659 Background: Carboplatin, docetaxel and trastuzumab (TCH) regimen yields substantial pathologic complete response (pCR) in operable HER2+ breast cancer. Eribulin mesylate (E) is a tubulin inhibitor recently shown to improve overall survival compared to taxanes and other agents in heavily pretreated metastatic breast cancer patients. This trial was designed to determine the maximum tolerated dose (MTD) of E in combination with CH (Phase I) and to determine efficacy and safety of the ECH regimen (Phase II) given as neoadjuvant therapy to early stage HER2+ breast cancer with pathologic complete response the primary endpoint. Methods: This is a multicenter prospective open label single arm trial. Eligible patients were operable stage IIA – IIIB HER2+ breast cancer, ECOG 0-1, normal LVEF, QTc < 480 msec, < grade 1 neuropathy and no history of invasive cancer within the past 3 years. Phase I planned up to 12 patients from 4 centers to 1 of 3 E dose cohorts, with pts treated at the MTD also evaluable for Phase II. Starting dose level 0 was 1.1 mg/m2 with escalation to dose level +1 at 1.4 mg/m2 and de-escalation to dose level -1 at 0.9 mg/m2 if necessary. ECH was given IV for six 3-week cycles with E d1 and d8; C AUC 6 d1; and H 8 mg/kg loading dose d1C1 and 6 mg/kg d1C2-C6. H is scheduled to continue after surgery to complete 1 year of treatment. C1 dose limiting toxicities (DLTs) were defined as: grade 4 thrombocytopenia, anemia, or neutropenia lasting > 5 days; any grade 3-4 non-hematologic toxicity attributable to E, C, H, or the combination; inability to deliver all three agents at assigned dose and schedule. Standard 3+3 dose escalation design was used. At present, 6 patients have been enrolled at dose 0 and 6 have been enrolled at dose +1. The MTD for E has not yet been determined. Phase II has planned enrollment of 44 additional patients from 8 centers with primary endpoint rate of pCR at surgery to be performed 4-8 weeks after completion of ECH and secondary endpoints of safety to include peripheral neuropathy and cardiac toxicity at treatment completion and 1 year follow up. Clinical trial information: NCT101388647.

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