HER2-negative Population Research Articles

Abstract PS06-03: Differences in ctDNA genomic profiles and outcomes of Black and White patients with metastatic breast cancer: results from a large multicenter consortium

Abstract Background: Black breast cancer patients have a well-documented survival disparity when compared to White patients. It is imperative to explore the reasons for this disparity from both a socioeconomic and biological perspective. Prior studies evaluating somatic genetic differences have primarily focused on tumor tissue analysis, which could be limited by inter- and intra-tumor heterogeneity. Circulating tumor DNA (ctDNA) testing allows for non-invasive detection of these heterogenous somatic mutations in the peripheral blood. We hypothesized that there could be differences in cancer-specific genetic profiles across Black and White patients with metastatic breast cancer (MBC), and that these differences may impact treatment response and clinical outcomes. Methods: This retrospective cohort study included a total of 1327 patients with MBC who were treated at Washington University in St. Louis (N=474 patients), Massachusetts General Hospital (N=412), and Northwestern University (N=441). All patients underwent ctDNA profiling using the commercially available Guardant360 assay. Race information was patient-reported, and ancestry data were not available. Descriptive analysis of clinical variables and pathway variants was performed. Univariate and multivariate analyses were done to evaluate single gene mutations and genetic pathways in both the entire cohort and the hormone-receptor positive (HR+), HER2-negative population (HR+/HER2-). The potential prognostic impact of these somatic mutations was assessed through multivariate analysis in both White and Black patient populations. Results: The cohort of 1327 patients included 1057 White patients (79.6%) and 140 Black patients (10.5%). The remaining patients (9.9%) were not included in the analysis due to low numbers. Black patients had significantly higher rates of GATA3 single nucleotide variants (snv) (OR 2.13, 95% CI 1.07-4.25, P=0.03), PTPN11 snv (OR 7.90, CI 1.10-56.56, P=0.04), and CCND2 copy number variants (cnv) (OR 3.78, CI 1.51-9.45, P=0.004). These alterations were also significantly more common in Black patients in the HR+/HER2- population (N = 812) for GATA3 snv (OR 2.28, CI 1.09-4.76, P=0.028), PTPN11 snv (OR 16.60, CI 1.49-184.93, p=0.022), and CCND2 cnv (OR 4.17, CI 1.02-16.97, P=0.046). Multivariate analysis confirmed that GATA3 snv (OR 2.23, CI 1.12-4.45, P=0.023) and CCND2 cnv (OR 3.97, CI 1.59-9.94, P=0.003) were significantly more common in Black patients in both the full cohort and HR+/HER2- subset. Mutations in the PI3K pathway were more prevalent in White patients, but this difference was not statistically significant in univariate or multivariate analysis. Overall survival (OS) from time of ctDNA collection was significantly worse in Black patients compared to White patients when corrected for lines of therapy and sites of metastasis (median 22 vs. 29 months, log-rank test, P=0.03). Among HR+/HER2- patients specifically, worse prognosis in White patients was associated with TP53 snv (HR 1.55, CI 1.19-2.01, P=0.001), NF1 snv (HR 1.99, CI 1.11-3.56, P=0.021), MYC cnv (HR 1.76, CI 1.09-2.87, P=0.02), PIK3CA cnv pathway (HR 1.69, CI 1.07-2.66, P=0.024), and MYC cnv pathway (HR 1.85, CI 1.15-2.97, P=0.011). No significant gene mutation or pathway association was found in Black patients. Prognostic differences in the cohort based on clinical, pathological, and treatment history were also explored and will be presented. Discussion: To our knowledge, this is the largest clinical genomic dataset examining ctDNA differences across Black and White patients. Our findings revealed that Black patients had higher frequencies of GATA3 snv and CCND2 cnv. The shorter OS observed in Black patients in our study aligns with previous studies and is likely multifactorial, especially given the early separation of the survival curves. Future research should focus on both socioeconomic and genetic factors to explain this disparity. Citation Format: Emily Podany, Lorenzo Foffano, Lorenzo Gerratana, Arielle Medford, Katherine Clifton, Whitney Hensing, Renee Morecroft, Marko Velimirovic, Ami Shah, Carolina REDUZZI, Laura Munoz Arcos, Charles S. Dai, Jennifer Keenan, Elyssa Denault, Foluso Ademuyiwa, Fabio Puglisi, Cynthia Ma, Aditya Bardia, Massimo Cristofanilli, Andrew Davis. Differences in ctDNA genomic profiles and outcomes of Black and White patients with metastatic breast cancer: results from a large multicenter consortium [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS06-03.

Abstract 3380: HER2 overexpression induces breast tumorigenesis in a non cell autonomous manner by inducing oxidative stress in the tissue microenvironment

Abstract Breast cancer is the most common cancer type in the world. Approximately 70% of pre-malignant breast tumours, known as ductal carcinoma in situ (DCIS), and 20% of invasive breast tumours overexpress HER2. Although molecular mechanisms of HER2 function in breast tumour cells have been extensively studied, our knowledge on how HER2 drives breast tumourigenesis at its pre-malignant stage is quite limited. Here, we investigate the HER2-overexpression driven cellular events at the earliest stages of breast tumourigenesis using in vitro, in vivo and ex vivo models. Using mouse models of HER2+ breast cancer and clinical samples of patients with DCIS, we showed that breast cancer stem cells (BCSCs) reside in HER2-negative population of tumour cells and arise from a HER2-negative cell-of-origin. Proteomics and metabolomics analyses of mammary ducts isolated from the MMTV-Neu mice at the pre-cancerous stage showed that HER2/Neu overexpression alters the energy metabolism in mammary epithelial cells in vivo. Furthermore, we have observed an accumulation of reactive oxygen species levels in pre-cancerous mammary ducts, which consequently causes oxidative stress induction and DNA damage in both HER2-positive and HER2-negative epithelial cells. Collectively, our findings indicate that HER2 overexpression in normal mammary epithelia may lead to a genotoxic tissue microenvironment that may consequently result in the accumulation of further somatic mutations in HER2-negative cell populations, which contain BCSCs and their cell-of-origin. Our findings therefore illustrate a novel mechanism explaining the HER2-driven breast tumour initiation and thus provide new avenues of research for developing novel preventive approaches against breast cancer. Citation Format: Sevim Beyza Gurler, Oliver Wagstaff, Lili Dimitrova, Fuhui Chen, Robert Pedley, William Weston, Ian Donaldson, Brian A. Telfer, David Novo, Kyriaki Pavlou, George Taylor, Yaqing Ou, Kaye Williams, Andrew Gilmore, Keith Brennan, Ahmet Ucar. HER2 overexpression induces breast tumorigenesis in a non cell autonomous manner by inducing oxidative stress in the tissue microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3380.

56P Association between HER2 expression level and prognosis using RT-PCR in HER2-low breast cancer

The variation and heterogeneity of conventional immunohistochemistry (IHC) or in situ hybridization (ISH) techniques for measuring HER2 has long been pointed out, and the method of testing for HER2 has been discussed for the selection of appropriate treatment. Therefore, we compared HER2 expression in RT-PCR using OncotypeDX have correlation with conventional IHC, and evaluated HER2 expression in RT-PCR as a prognostic factor in HER2-negative early breast cancer. ER+/HER2- patients who underwent breast cancer surgery between 2004 and 2016 and underwent OncotypeDX testing were included. Data from 632 patients were collected and analyzed by retrospective chart review at 9 centers to determine if there was a correlation between HER2 expression by IHC and RT-PCR. HER2 expression was classified as negative, HER2-low, and positive when HER2 mRNA levels were ≤ 9.1, 9.2-11.4, and11.5≤, respectively, based on the median mRNA level in HER2 negative in IHC. Survival curves were estimated using the Kaplan-Meier method with a log-rank test between the three groups. The median age of the 632 patients was 51 years. Of the 632 patients, 311(49.2%) were pStage I, the 309 (48.9%) were pStage II, and 11(1.7%) were pStage III. 127 (20%) patients received postoperative chemotherapy, and 54 (8.5%) patients had relapse. HER2 IHC rates were HER2 0: 166 (26.3%), 1+: 304 (48.1%), and 2+: 162 (25.6%). There was a weak correlation between the IHC and RT-PCR methods for HER2 expression (Spearman rank correlation P<0.001, r=0.33). The recurrence rates of IHC 0, 1+, and 2+ were 1.8%, 3.9%, 2.6%, respectively. There was no statistically significant difference in DFS between the three groups of HER2 expression by the IHC method (P=0.59). In addition, in the study of HER2 expression and prognosis by RT-PCR, the patients were divided into HER2 negative: 269, HER2-low: 357, and HER2 positive: 1. There was no statistically significant difference between the three groups (P=0.832). The recurrence rates were 3.9%, 4.4%, and 0%, respectively. In the analysis of HER2 expression, there was a weak correlation between IHC and RT-PCR mRNA expression levels; in the HER2-negative population, RT-PCR mRNA expression of HER2 was not a prognostic factor in early breast cancer.

Clinicopathological characteristics and prognosis of early-stage HER2 low-expression breast cancer: A single-center retrospective study.

Owing to the emergence of drugs targeting human epidermal growth factor receptor 2 (HER2), remarkable prognostic enhancement has been seen for patients with HER2-positive breast carcinoma. However, anti-HER2 medicines are applicable merely to individuals with HER2-positive tumors, and the benefit for those with low HER2 expression is unclear. The DESTINY-Breast04 phase III and RC48 clinical trial results showed the benefit of antibody-drug couples for low HER2-expressing individuals with breast carcinoma, challenging the traditional dichotomy between HER2-negative and -positive tumors. Hence, the purposes of the present work are to explore the clinicopathological traits and prognostic differences in the HER2-low expression Chinese population with early-stage breast carcinoma. Data from the database of the Breast Center of the Affiliated Hospital of Qingdao University were collected from January 2008 to December 2017. We screened a total of 4,598 patients, of which 2,837 had HER2-0 tumors and 1,761 had HER2-low tumors. Additionally, clinicopathological characteristics, survival, and prognostic information were obtained. Difference comparisons were made between HER2-0 and HER2-low groups regarding the clinical traits and outcomes. We enrolled 4598 patients, with the HR-positive subjects suffering from HER2-low breast carcinoma higher in proportion than the HR-negative patients. In contrast to HER2-0 tumors, the HER2-low tumors were linked to an older median age at diagnosis, T1 tumors, N1 stage, a higher Ki-67 index, as well as inferior histological grade. Insignificant inter-group difference was noted regarding overall survival (OS), although the HER2-0 group exhibited better disease-free survival (DFS) than the HER2-low group for the entire (P = 0.003), lymph node-negative (P = 0.009) and HR-positive (P = 0.007) populations. According to the multivariate regression finding, low HER2 expression was an inferior DFS prognostic factor in the HER2-negative population with early-stage breast cancer (HR,1.33;95% CI, 1.06-1.66; P = 0.013). The clinical traits of the HER2-low carcinomas differed from those of HER2-0 tumors. Despite the insignificant inter-group difference in OS, the differences in DFS were found for the overall, lymph node-negative and HR-positive subjects, suggesting the possibility of HER2-low as an inferior prognostic factor for disease progression in early-stage breast cancer.

In Real Life, Low-Level HER2 Expression May Be Associated With Better Outcome in HER2-Negative Breast Cancer: A Study of the National Cancer Center, China.

BackgroundTo characterize the clinical and pathological features and survival of patients with human epidermal growth factor receptor 2 (HER2)-low breast cancer in China.MethodsThe China National Cancer Center database was used to identify 1,433 metastatic breast cancer patients with HER2-negative disease diagnosed between 2005 and 2015. Clinicopathological features, survival, and prognosis information were extracted. Overall survival (OS) was estimated using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors associated with OS were analyzed using Cox regression model with 95% confidence interval (95% CI).ResultsThere were 618 (43.1%) and 815 (56.9%) HER2-low and HER2-zero tumors out of 1,433 tumors, respectively. The proportion of hormone receptor (HR)-positive tumors was significantly higher in HER2-low tumors than in those with HER2-zero tumors (77.8% vs. 69.2%, p < 0.001). Patients with HER2-low tumors survived significantly longer than those with HER2-zero tumors in the overall population (48.5 months vs. 43.0 months, p = 0.004) and HR-positive subgroup (54.9 months vs. 48.1 months, p = 0.011), but not in the HR-negative subgroup (29.5 months vs. 29.9 months, p = 0.718). Multivariate regression analysis revealed that HER2-low tumors were independently associated with increased OS in HER2-negative population (HR: 0.85, 95% CI: 0.73–0.98, p = 0.026).ConclusionOur findings demonstrate that HER2-low tumors could be identified as a more distinct clinical entity from HER2-zero tumors, especially for the HR-positive subgroup. A more complex molecular landscape of HER2-low breast cancer might exist, and more precise diagnostic algorithms for HER2 testing could be investigated, thus offering new therapeutic targets for breast cancer treatment.

Abstract PD5-08: Tumor immune-cell activity assessed by RNAseq is an independent predictor of therapy response and prognosis after neoadjuvant chemotherapy in HER2 negative breast cancer patients - An analysis of the GeparSepto trial

Abstract Background: Tumor immune markers such as tumor infiltrating lymphocytes (TILs) or expression-based profiles have been correlated with both response to neoadjuvant chemotherapy and prognosis in early breast cancer (BC) patients. Some chemotherapies, such as paclitaxel, lead to the development of TILs and in some cases, suppression of regulatory T-cells. Therefore, assessment of the tumor microenvironment (TME) could provide important information for clinical decision-making. The aim of this study was to test if RNAseq-based TME classification of BC tumors is predictive of pathological complete Response (pCR) and prognosis in the neoadjuvant GeparSepto (G7) trial (NCT01583426). Methods: We performed a retrospective-prospective analysis of a subset of 810 subjects of the total of 1207 patients of the G7 trial. In G7 HER2-negative early high-risk BC patients were studied to determine if nab-paclitaxel is superior to solvent-based paclitaxel. In addition to the taxane paclitaxel, both treatment arms received epirubicin plus cyclophosphamide before surgery. For this analysis, a subset of 279 HER2 negative patients with sufficient quality of pretherapeutic core biopsies to perform whole-transcriptome RNAseq (~200x106 reads per tumor) was used. Based on RNAseq data, immune activity classification was provided by ImmunityBio (Culver City, CA) by comparison of expression of 23 immune-cell-specific gene signatures as described by Bindea et al. (Immunity, 2013) to those from a reference population of 1467 similarly-profiled unselected tumor samples from a large tumor database (NantOmics, Culver City, CA). Unsupervised hierarchical clustering of inferred immune activities revealed 3 distinct groups termed “hot”, “warm”, and “cold” clusters. Logistic regression analysis based on age, trial arm, tumor size, nodal status, Ki-67, hormone-receptor (HR) status and immune activity cluster (hot/warm vs. cold) as independent variables was performed to predict pCR (ypT0/ypN0). Cox regression analysis with the same covariates was also performed to predict disease-free survival (DFS) and overall survival (OS). Results: Of the 279 patients, 67 had a pCR (24%). The analyzed subset was similar to the main HER2 negative population (pCR-rate: 22%). Patients with a “hot/warm” or “cold” immune activity assessment had a pCR in 30% and 13% of the cases, respectively. The odds-ratio of the multivariate logistic regression analysis was 2.17 (95% CI: 1.00-4.71, p=0.0512). With regard to DFS and OS, T follicular helper cell B-cell, and T-cell signatures seemed to play a prominent role, and the hazard ratios (also “hot/warm” vs. “cold”) for the multivariate analyses were 0.38 (95% CI: 0.21-0.66; p=0.0007) and 0.34 (95%CI: 0.16-0.72, p= 0.0045), respectively. Within the 23 individual immune-cell-specific gene signatures, CD56dimNatural Killer (NK), type 1 helper T-cells, and CD8+ T-cell signatures seemed to be closely associated with achievement of a pCR. RNAseq-based deconvolution of immune-cell activity was corroborated by IHC-based TIL scoring. Immune-hot/warm patients had more intratumoral lymphocytes compared to cold tumors (mean: 11.6% vs. 4.9%, p&amp;lt;0.0001). Specifically, adaptive immunity gene signatures (i.e. CD8+ T-cell signature, CD56dim NK, and Th1) were moderately correlated with the percentage of TILs (rho correlation coefficients from 0.42 to 0.53). Conclusion: TME profiling by RNAseq may be an independent biomarker useful for predicting response to and prognosis after neoadjuvant chemotherapy including taxanes and anthracyclines in early HER2 negative high-risk BC. These results indicate that the further development of this biomarker could be of direct clinical importance. Citation Format: Peter A Fasching, Carsten Denkert, Stephen Benz, Karsten E Weber, Christopher Szeto, Jan Budczies, Andreas Schneeweiss, Elmar Stickeler, Sabine Schmatloch, Christian Jackisch, Thomas Karn, Hans Peter Sinn, Mathias Warm, Marion van Mackelenbergh, Sharooz Rabizadeh, Christian Schem, Ernst Heinmöller, Volkmar Müller, Frederik Marmé, Patrick Soon-Shiong, Valentina Nekljudova, Michael Untch, Sibylle Loibl. Tumor immune-cell activity assessed by RNAseq is an independent predictor of therapy response and prognosis after neoadjuvant chemotherapy in HER2 negative breast cancer patients - An analysis of the GeparSepto trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-08.

Abstract P5-13-06: Analysis of barriers to clinical trial accrual in an NCI-designated comprehensive cancer center: Results of identifying clinical trial gaps

Abstract Background: NCI-designated centers struggle to meet the 10% minimum accrual benchmark even for common malignancies such as breast cancer. The University of New Mexico Comprehensive Cancer Center (UNMCCC) average annual breast cancer trial accrual rate is approximately 11%, despite an average of 20 open breast cancer trials. Many published barriers were perceived to account for UNMCCC's low accrual including suboptimal screening, patients' unwillingness to participate, and disparities arising from socioeconomic and cultural barriers related to the large minority patient population. We sought to identify the true barriers to breast cancer therapeutic trials accrual to strategically formulate targeted solutions. Methods: In 2016, a retrospective study was performed to review all breast cancer patients from UNMCCC's 2014 NCI Data Table 3. Barriers were classified into (a) trial specific, in which no trial was available or the patient was ineligible (b) patient specific, in which an appropriate trial was available but the patient declined participation (c) provider specific, in which screening was not documented. Results: 145 cases were retrospectively evaluated. 6% declined participation, 13% were ineligible and 4% were not screened. Only 11% were enrolled in the 21 open trials. No trial was available for 66% of patients. Out of this group, the majority of cases (68%) were stage 0/ I/ II (DCIS 12% LCIS 4%, stage I/II node negative, HR+, Her2- 52%), 17% were triple negative and 15% were HER2 positive. The findings showed that despite the extensive clinical trial menu, the trials did not in fact adequately match the majority of the patient population who largely had early stage disease. This was identified as the main barrier to accrual. This resulted in a change in trial prioritization. Previously, the majority of trials were for advanced disease. From 2016-2018, the priority shifted to opening trials focused on early stage HR+, Her2 negative population. Investigator initiated, pharmaceutical, NCTN trials and symptom control trials for this population were opened. As of December 2017, Data Table 3 accrual showed that 19% (70/353) new breast cancer patients were enrolled. This represents an increase in accrual from 11% to 19 %. Of these, 28% (20/70) had early stage HR+ Her2 negative disease. As of 2018, therapeutic trials that include early stage HR+, Her2 -, node negative disease now comprise 30% of the UNMCCC breast cancer trial menu. Conclusion: Detailed analysis of UNMCCC's breast cancer Data Table 3 showed that contrary to prior perceptions, the main accrual barrier was not ineffective screening, patient ineligibility or unwillingness to participate. The main barrier was that the extensive trial menu did not match the patient population. A large gap in the clinical trial menu was identified. Published barriers to clinical trial accrual may not necessarily hold true for a specific institution. A disease-specific root cause analysis can facilitate development of tailored solutions. A shift in strategy in trial prioritization resulted in an increase in annual breast cancer trial accrual from 11% to 19%. Citation Format: Dayao Z, Nemunaitis J. Analysis of barriers to clinical trial accrual in an NCI-designated comprehensive cancer center: Results of identifying clinical trial gaps [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-13-06.

Evaluation of the prognostic value of all four HER family receptors in patients with metastatic breast cancer treated with trastuzumab: A Hellenic Cooperative Oncology Group (HeCOG) study.

In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), mRNA and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Central review of HER2 status by IHC and fluorescence in situ hybridization revealed that of the 227 patients, only 139 (61.2%) were truly HER2-positive. Regarding the 191 patients treated with trastuzumab as first-line therapy, median time to progression (TTP) was 15.3 and 10.4 months for HER2-positive and HER2-negative participants, respectively, whereas median survival was 50.4 and 38.1 months, respectively. In HER2-positive patients, high HER3 mRNA expression was of favorable prognostic significance for TTP and survival (HR = 0.43, 95% CI 0.21–0.88, Wald’s p = 0.022 and HR = 0.43, 95% CI 0.21–0.88, p = 0.021, respectively), while EGFR copy gain and EGFR protein expression were associated with higher risk for disease progression in HER2-negative patients (HR = 3.53, 95% CI 1.19–10.50, p = 0.023 and HR = 3.37, 95% CI 1.12–10.17, p = 0.031, respectively). Positive HER3 protein expression was a favorable factor for TTP in HER2-negative patients (HR = 0.43, 95% CI 0.22–0.84, p = 0.014). In the multivariate analysis, only EGFR copy gain retained its prognostic significance for TTP in the HER2-negative population (HR = 3.96, 95% CI 1.29–12.16, p = 0.016), while high HER3 mRNA expression retained its favorable prognostic significance for TTP in the HER2-positive subgroup (HR = 0.47, 95% CI 0.23–0.99, p = 0.048). The present study suggests that EGFR copy gain represents a negative prognostic factor for TTP in HER2-negative patients with metastatic breast cancer treated with trastuzumab. In addition, high HER3 mRNA expression appears to be of favorable prognostic significance for TTP in HER2-positive patients. Given the small number of patients included in the current analysis and the retrospective nature of the study, our findings should be validated in larger cohorts.

Abstract P1-07-24: Evaluation of the prognostic value of all four HER family receptors in patients with metastatic breast cancer treated with trastuzumab: A hellenic cooperative oncology group (HeCOG) study

Abstract Background-aim: Metastatic breast cancer (MBC) is an incurable disease. Trastuzumab, a recombinant humanized monoclonal antibody, was found to significantly prolongsurvival of patients with metastatic HER2 over-expressing and/or amplified breast cancer. In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Methods: Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), transcriptional profiling and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Results: Central review of HER2 status by IHC and fluorescence in situ hybridization revealed that of the 227 patients, only 139 (61.2%) were truly HER2-positive. Regarding the 191 patients treated with trastuzumab as first-line therapy, median time to progression (TTP) was 15.3 months and 10.4 months for HER2-positive and HER2-negative participants, respectively. Median survival was 50.4 months for HER2-positive and 38.1 months for HER2-negative patients. In HER2-positive patients, high HER3 mRNA expression was of favorable prognostic significance for TTP and survival (HR=0.43, 95% CI 0.21-0.88, Wald's p=0.022 and HR=0.43, 95% CI 0.21-0.88, p=0.021, respectively), while EGFR copy gain and EGFR protein expression were associated with higher risk for disease progression in HER2-negative patients (HR=3.53, 95% CI 1.19-10.50, p=0.023 and HR=3.37, 95% CI 1.12-10.17, p=0.031, respectively). Positive HER3 protein expression was a favorable factor for TTP in HER2-negative patients (HR=0.43, 95% CI 0.22-0.84, p=0.014). In the multivariate analysis, only EGFR copy gain retained its prognostic significance for TTP in the HER2-negative population (HR=4.81, 95% CI 1.52-15.82, p=0.008), while none of the examined factorsretained their prognostic significance for TTP or survival in the HER2-positive subgroup. Conclusions: The present study suggests that EGFR copy gain represents a negative prognostic factor for TTP in HER2-negative patients with metastatic breast cancer. In addition, high HER3 mRNA expression appears to be of favorable prognostic significance for TTP and survival in HER2-positive patients. Given the small number of patients included in the current analysis and the retrospective nature of the study, our findings should be validated in larger cohorts. Citation Format: Koutras A, Kotoula V, Koliou G-A, Kouvatseas G, Christodoulou C, Pectasides D, Batistatou A, Bobos M, Tsolaki E, Papadopoulou K, Pentheroudakis G, Papakostas P, Pervana S, Petraki K, Chrisafi S, Razis E, Psyrri A, Bafaloukos D, Kalogeras KT, Kalofonos HP, Fountzilas G. Evaluation of the prognostic value of all four HER family receptors in patients with metastatic breast cancer treated with trastuzumab: A hellenic cooperative oncology group (HeCOG) study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-24.

Estrogen Receptor Expression in 21-Gene Recurrence Score Predicts Increased Late Recurrence for Estrogen-Positive/HER2-Negative Breast Cancer.

To identify the individual genes or gene modules that lead to the OncoptypeDx 21-gene recurrence score's reduced performance after 5 years and thereby identify indices of residual risk that may guide selection of patients for extended adjuvant therapy. We conducted a retrospective assessment of the relationship between (i) the individual genes and gene modules of the Recurrence Score and (ii) early (0-5 years) and late (5-10 years) recurrence rates in 1,125 postmenopausal patients with primary estrogen receptor-positive breast cancer treated with anastrozole or tamoxifen in the Arimidex, Tamoxifen, Alone or Combined (ATAC) randomized clinical trial. In the HER2-negative population (n = 1,009), estimates of recurrence risk were similar between years 0-5 and 5-10 for proliferation and invasion modules but markedly different for the estrogen module and genes within it (all split at the median): for low estrogen module, annual recurrence rates were similar across the two time windows (2.06% vs. 2.46%, respectively); for high estrogen module, annual rates were 1.14% versus 2.72%, respectively (P interaction = 0.004). Estrogen receptor transcript levels showed inverse prediction across the time windows: HR, 0.88 (0.73-1.07) and 1.19 (0.99-1.43), respectively (P interaction = 0.03). Similar time-, module-, and estrogen-dependent relationships were seen for distant recurrence. Patients with tumors with high estrogen receptor transcript levels benefit most from 5 years' endocrine therapy but show increased recurrence rates after 5 years and may benefit from extended therapy. Improved prognostic profiles may be created by considering period of treatment and follow-up time.

High-Dose Chemotherapy With Autologous Hematopoietic Stem Cell Transplantation for High-Risk Primary Breast Cancer.

The efficacy of high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation for breast cancer (BC) has been an area of intense controversy among the medical oncology community. Over the last decade, due to the presentation of negative results from early randomized studies, this approach has not longer been considered an option by the vast majority of medical oncologists. This article is aimed to clarify what happened and where we are now in this not exhausted field. We critically revised the published literature regarding HDC in the setting of high-risk BC, including a recent meta-analysis using individual patient data from 15 randomized studies. A significant benefit by HDC in recurrence-free survival has been clearly documented in unselected patient populations. In HER2-negative population, particularly in the triple-negative disease, a positive effect of intensified therapy in overall survival is biologically plausible and supported by clinical evidence. Over the years HDC with support of adequate number of stem cells has become a safe treatment modality. The administration of higher doses of chemotherapy with stem cell support may still represent a therapeutic option (and not a recommendation) in selected BC patients. This approach should be investigated further.

PTEN Loss Is Associated with Worse Outcome in HER2-Amplified Breast Cancer Patients but Is Not Associated with Trastuzumab Resistance.

To investigate the clinical relevance of PTEN in HER2-amplified and HER2-nonamplified disease. We assessed PTEN status in two large adjuvant breast cancer trials (BCIRG-006 and BCIRG-005) using a PTEN immunohistochemical (IHC) assay that was previously validated in a panel of 33 breast cancer cell lines and prostate cancer tissues with known PTEN gene deletion. In the HER2-positive patient population, absence of tumor cell PTEN staining occurred at a rate of 5.4% and was independent of ER/PR status. In contrast, 15.9% of HER2-negative patients exhibited absence of PTEN staining with the highest frequency seen in triple-negative breast cancer (TNBC) subgroup versus ER/PR-positive patients (35.1% vs. 10.9%). Complete absence of PTEN staining in tumor cells was associated with poor clinical outcome in HER2-positive disease. Those patients whose cancers demonstrated absent PTEN staining had a significant decrease in disease-free survival (DFS) and overall survival (OS) compared with patients with tumors exhibiting any PTEN staining patterns (low, moderate, or high). Trastuzumab appeared to provide clinical benefit even for patients lacking PTEN staining. In the HER2-negative population, there were no statistically significant differences in clinical outcome based on PTEN status. This study is the largest to date examining PTEN status in breast cancer and the data suggest that the rate and significance of PTEN status differ between HER2-positive and HER2-negative disease. Furthermore, the data clearly suggest that HER2-positive patients with PTEN loss still benefit from trastuzumab.

Medical management of gastric cancer: a 2014 update.

Gastric cancer represents a serious health problem on a global scale. It is the second leading cause of cancer-related death worldwide. Novel therapeutic targets are desperately needed because the meager improvement in the cure rate of about 10% realized by adjunctive treatments to surgery is unacceptable as > 50% patients with localized gastric cancer succumb to their disease. Either postoperative chemoradiotherapy (United States), pre-and post-operative chemotherapy (Europe), and adjuvant chemotherapy after a D2 resection (Asia) can all be regarded as standards of care in the localized gastric cancer management. In metastatic disease the addition of trastuzumab to chemotherapy is standard of care in Her2 positive disease. In the HER2 negative population, the treatments remain limited. In the first line setting, the standard of care is a combination of fluoropyrimidine and platinum containing chemotherapy, with or without epirubicin or docetaxel. The results of targeted therapy trials have by and large been disappointing, but none of these trials looked at an appropriately enriched population. Finally there is a meager overall survival benefit in treating patients with metastatic disease in the second line setting, with either irinotecan, docetaxel or ramucirumab however none of these drugs have been compared head to head in a well-powered randomized controlled trial.

P3-14-11: Comparison of Two Nomograms To Predict Pathologic Complete Response to Neoadjuvant Chemotherapy – Evidence That HER2 Positive Tumors Need Specific Predictors.

Abstract Aim: The purpose of this study was to compare two different nomograms to predict pathologic complete response (pCR) to preoperative chemotherapy in an independent cohort of 200 patients with breast cancer. The first model was the MDACC nomogram published in 2005 and the other one was a nomogram based on the number of preoperative courses, Ki-67 and steroid hormone receptors expression published by Colleoni et al. in 2010 Patients and methods: Data from 200 patients with breast carcinoma treated with preoperative chemotherapy and operated at Tenon Hospital from 2001 to 2009 were collected. We calculated pCR rate predictions with the two nomograms and compare those predictions with outcome. Patients received between 4 and 8 course of anthracycline/taxanes based chemotherapy. More than 90% of patients with HER2 positive tumors received concomitant trastuzumab with taxanes. Model performances were quantified with respect to discrimination (evaluated by the areas under the receiver operating characteristics curves (AUC)) and calibration. Results: In the entire population, the AUC for the MDACC nomogram and the Colleoni nomogram were respectively 0.74 and 0.75. Both of them underestimated the pCR rate (p=0.02 and 0.0005). When excluding patients treated with trastuzumab, the AUC were 0.78 for both of them with no significant difference between the predicted and the observed pCR (p=0.14 and 0.15). When analyzing the specific population treated with trastuzumab as preoperative treatment, the AUC for the MDACC nomogram and the Colleoni nomogram were respectively 0.52 and 0.53. Conclusion: The MDACC and the Colleoni nomograms are accurate to predict the probability of pCR after preoperative chemotherapy in HER2 negative population but did not correctly predict pCR in HER2 positive patients who received trastuzumab. This suggests that response to preoperative chemotherapy including trastuzumab is biologically driven and that a specific nomogram or predictor for HER2 positive patients has to be developed. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-11.

Comparison of two nomograms to predict pathologic complete responses to neoadjuvant chemotherapy for breast cancer: evidence that HER2-positive tumors need specific predictors

The aim of this study is to compare two published nomograms, the "Institut Gustave Roussy/M.D. Anderson Cancer Center" (IGR/MDACC) and the Colleoni nomograms, in predicting pathologic complete responses (pCR) to preoperative chemotherapy in an independent cohort and to assess the impact of HER2 status. Data from 200 patients with breast carcinoma treated with preoperative chemotherapy were collected. We calculated pCR rate predictions with the two nomograms and compared the predictions with the outcomes. Sixty percent of the patients with HER2-positive tumors received trastuzumab concomitantly with taxanes. Model performances were quantified with respect to discrimination and calibration. In the whole population, the area under the ROC curve (AUC) for the IGR/MDACC nomogram and the Colleoni nomogram were 0.74 and 0.75, respectively. Both of them underestimated the pCR rate (P = 0.026 and 0.0005). When patients treated with trastuzumab were excluded, the AUC were excellent: 0.78 for both nomograms with no significant difference between the predicted and the observed pCR (P = 0.14 and 0.15). When the specific population treated with trastuzumab preoperatively was analyzed, the AUC for the IGR/MDACC nomogram and the Colleoni nomogram were poor, 0.52 and 0.53, respectively. The IGR/MDACC and the Colleoni nomograms were accurate in predicting the probability of pCR after preoperative chemotherapy in the HER2-negative population but did not correctly predict pCR in the HER2-positive patients who received trastuzumab. This suggests that responses to preoperative chemotherapy, including trastuzumab, are biologically driven and that a specific nomogram or predictor for HER2-positive patients has to be developed.

A Phase II Study of Weekly Nanoparticle Albumin-Bound Paclitaxel With or Without Trastuzumab in Metastatic Breast Cancer

Introduction Weekly administration of nanoparticle albumin-bound ( nab) paclitaxel as a first-line treatment for metastatic breast cancer (MBC) has not been fully investigated. The addition of trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is less understood. This phase II study evaluated the efficacy and safety of weekly nab paclitaxel in the first-line MBC setting. Patients whose tumors overexpressed HER2 also received trastuzumab. Patients and Methods Patients with locally advanced or metastatic breast cancer received nab paclitaxel (125 mg/m 2) by 30-minute intravenous infusion weekly for 3 of 4 weeks. Patients who were HER2-positive received concurrent trastuzumab. Results Seventy-two patients were enrolled; HER2 expression was detected in 22 patients. The overall response rate (ORR) was 42.2% (95% CI, 30%–55%); 5 patients had a complete response (CR) and 22 patients had a partial response (PR). Additionally, 17 patients experienced stable disease (SD), providing an overall benefit (CR + PR + SD) of 68.8%. Patients with HER2-positive tumors had an ORR of 52.4%; the ORR was 38.1% in the HER2-negative population ( P = .3). Median progression-free survival was 14.5 months (range, 1–49.3 months) and survival rates at 1 year and 2 years were 69% and 62%, respectively. The most commonly observed toxicities were pain (64%), fatigue (58%), sensory neuropathy (54%), infection (46%), nausea (38%), alopecia (33%), and anemia (33%). Conclusion Our findings demonstrate that weekly nab paclitaxel has a favorable safety profile and is well tolerated as a first-line treatment for MBC. An ORR of 42% and an overall benefit of 69% is extremely encouraging, particularly in the HER2-positive population where 52% of patients responded.

Reply to M. Rosman et al

We welcome the opportunity to respond to the correspondence from Rosman et al in reference to our article assessing the performance of the Oncotype DX Recurrence Score (RS) in patients from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. As requested, we have examined our data for evidence of the performance of the RS in patients with human epidermal growth factor receptor 2 (HER2) –negative disease. In our earlier analysis, we fitted a multivariate Cox proportional hazards model in a total of 1,178 patients (872 with node-negative [N0] disease; 306 with node-positive [N ] disease). In this set, the hazard ratios (HRs) for a 50-point increment in the RS element of the model were 5.25 (95% CI, 2.84 to 9.78; 2 22.7; P .001) for patients with N0 disease and 3.47 (95% CI, 1.64 to 7.38; 2 9.4; P .002) for patients with N disease. In our new analyses, the patient numbers are reduced by 18 to 1,160 (855 N0; 305 N ) because of missing HER2 status. The HRs for the RS element are nearly identical to the old values, being 5.27 and 3.38, respectively. There were 1,038 HER2-negative tumors in 764 patients with N0 disease and 274 patients with N disease. HRs for the RS element of the model for these patients are 6.08 (95% CI, 2.22 to 16.66; 2 10.8; P .001) for patients with N0 disease and 5.18 (95% CI, 1.64 to 16.37; 2 7.3; P .007) for patients with N disease. Thus the estimated HRs for the RS are somewhat larger for the HER2-negative group, and although the statistical significance of the effect of adding RS to the clinicopathologic elements of the model is less than for the whole population because of fewer events, the effect remains highly significant. The proportions of patients in the RS low-, intermediate-, and high-risk groups were 57%, 28%, and 15%, respectively, for the combined HER2 negative and HER2 positive. The respective figures for the HER2-negative population were 62%, 28%, and 10%. These analyses indicate that the RS adds substantial information on the risk of distant recurrence when restricted to the HER2negative population.

Lapatinib Combined With Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor–Positive Metastatic Breast Cancer

Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.

Phase II trial of neoadjuvant sequential FEC100 followed by docetaxel and capecitabine for HER2-negative locally advanced breast cancer (LABC): A multicenter study from British Columbia

598 Background: Anthracyclines and taxanes are now standard of care for LABC. Phase III trials have demonstrated pathological complete responses of the breast (pCR) of 20–34% in studies of primary operable and LABC. Recent trials in the HER-2 negative population reported pCR rates of 20–29%.We have completed a multi-centre phase II trial of a neoadjuvant sequential anthracycline and taxane combination regimen in a HER-2 negative LABC population. Methods: Women with HER-2 negative stage IIB-IIIC breast cancer were enrolled. Treatment consisted of 4 cycles of FEC100 (5-FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2) followed by 4 cycles of XT (docetaxel 75 mg/m2 and capecitabine 1,000 mg/m2 PO BID x 14 days q3 weekly). Hormone receptor positive cases were prescribed standard endocrine therapy. A correlative translational component with baseline and interval biopsies and serum collection was also performed. Results: A total of 51 patients (27% stage IIB; 43% IIIA; 20% IIIB; and 10% IIIC) were accrued across 4 BCCA centres from November 2004-December 2007. Median age was 54 years (33–67 years). 59% of tumours were ER positive. There were no primary progressors on FEC100, though 2 patients had significant toxicities requiring early discontinuation. 3 patients (6%) developed clinical progression on XT. The majority of patients (79%) on XT required a dose reduction or delay. There were 5 episodes (10%) of febrile neutropenia. 15 patients (29%) underwent adjuvant radiotherapy prior to surgery. The pCR rate (breast and axilla) for the entire study population was 22% (11/51). In the ER+ and triple negative subtypes the pCR (breast and axilla) was 13% and 42%, respectively. Conclusions: This multi-centre phase II trial demonstrates activity for neoadjuvant anthracyclines followed by combination docetaxel/capecitabine in a HER-2 negative LABC population. Though the pCR rate was greater in the triple negative cohort, significant improvements are still required across the biological subtypes in HER-2 negative LABC. [Table: see text]

Neoadjuvant bevacizumab, docetaxel and capecitabine combination therapy for HER2/neu-negative invasive breast cancer: Efficacy and safety in a phase II pilot study

Purpose To evaluate the triplet combination of bevacizumab, capecitabine and docetaxel (XTA) as neoadjuvant therapy for breast cancer. Experimental design Patients with invasive, HER2-negative, nonmetastatic breast cancer (T2–4c >2 cm) and no prior systemic therapy received six 21-day cycles of XTA (bevacizumab 15 mg/kg, day 1, cycles 1–5; docetaxel 75 mg/m 2, day 1 of each cycle; capecitabine 950 mg/m 2 twice daily for 14 days of each cycle). Patients underwent surgery 2–4 weeks after completing XTA, followed by radiotherapy, chemotherapy and hormone therapy according to institution guidelines. Pathologic complete response (pCR), the primary endpoint, was defined as no evidence of invasive tumour in the final surgical sample. Secondary endpoints included rates of clinical response and breast-conserving surgery and safety. Results Median age of the 18 enrolled patients was 48 years (range 34–69). Most patients (72%) received six cycles of neoadjuvant therapy. pCR rate was 22% (95% confidence interval [CI]: 6–48). Nine of the patients without pCR achieved clinical partial response, giving a 72% overall clinical response rate (95% CI: 47–90). Fifteen patients underwent breast-conserving surgery (83%; 95% CI: 59–96). One additional patient had breast-conserving surgery, followed by mastectomy 1 month later. The remaining 2 patients underwent modified radical mastectomy. XTA was reasonably well tolerated, with no unexpected toxicities or treatment-related deaths. Conclusions The 22% pCR rate in a HER2-negative population suggests that addition of bevacizumab increases the activity of neoadjuvant capecitabine–docetaxel. Further evaluation of this regimen in early breast cancer is recommended.