Significant Difference In pCR Research Articles

Abstract PO3-03-05: Clinical outcomes in early-stage TNBC according to HER2-low status

Abstract Background: Clinical outcomes according to HER2 immunohistochemistry (IHC) in patients with early-stage HER2-negative breast cancer have differed across studies. For early-stage TNBC (eTNBC), less representation of this subtype in cohorts studied to date has limited interpretation of results. We sought to evaluate outcomes according to HER2 IHC in a multi-institutional cohort of patients (pts) with eTNBC who received neoadjuvant therapy (NAT). Methods: Pts diagnosed with stage I-III TNBC (including HR-low; ER and PR < 10%) who received NAT and underwent surgery between 1/1/16-6/30/19 were identified across three institutional prospective databases. HER2 was defined as low (1+ or 2+/ISH non-amplified) or HER2-0 according to local testing at diagnosis. Pathological complete response (pCR) was defined as no residual invasive disease in breast and axilla. Multivariable logistic regression was used to compare pCR rates (HER2-low vs HER2-0) adjusting for age at diagnosis, race, anatomic clinical stage, germline BRCA1/2 (gBRCA), histology, HR status and receipt of anthracycline and taxane NAT. Recurrence-free (RFS), distant recurrence-free (DRFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Multivariable Cox proportional hazards model was used to estimate adjusted hazard ratios. Results: A total of 978 pts were identified of which 388 (39.7%) had HER2-low and 590 (60.3%) had HER2-0 tumors at diagnosis. Median age was 50.3 (range: 21.0-83.4) yrs. 174 (17.8%) pts had HR-low tumors. 142 (14.5%) pts had a known gBRCA mutation. 790 pts (80.8%) received anthracycline- and taxane NAT. No significant differences were observed in age, race, gBRCA, histology, HR status (low vs negative), clinical tumor size, or type of NAT between HER2-low and HER2-0 groups. Clinical nodal positivity was higher in HER2-low (55.2%) vs HER2-0 (46.6%), p=0.011. No significant difference in pCR was observed between HER2-low (32.0%) and HER2-0 (32.7%) groups, adjusted p=0.928. Among pts with residual disease (RD) post-NAT with HER2 IHC also available in the RD sample, 244/363 (67.2%) had concordant HER2 status. 70/225 (31.1%) of HER2-0 tumors at diagnosis had IHC expression post-NAT (66 HER2-low, 4 HER2-positive); 48/138 (34.8%) of HER2-low tumors at diagnosis were HER2-0 post-NAT. At a median follow-up of 3.1 yrs, RFS did not significantly differ between HER2-low vs HER2-0 pts with pCR (p=0.368) or in those with RD post-NAT (p=0.573). Similarly, DRFS did not differ according to HER2 category for pts with pCR (p=0.509) or RD (p=0.812), nor did OS for pts with pCR (p=0.514) or RD (p=0.285) (Table 1). Conclusion: In a large cohort of pts with eTNBC treated with NAT, HER2-low status was not associated with pCR or survival after adjusting for clinical factors. High rate of discordance in HER2 IHC between diagnostic and RD post-NAT was observed, highlighting the importance of repeat IHC testing in serial samples given the development of antibody drug conjugates for HER2-low breast cancer. Table 1. RFS, DRFS and OS by HER2 expression Citation Format: Ana Garrido-Castro, Danielle Brandes Zakon, Qingchun Jin, Michael Grimm, Akshara Singareeka Raghavendra, Melissa Hughes, Mathew Cherian, Julie Vincuilla, Tonia Parker, Paolo Tarantino, Elizabeth Mittendorf, Tari King, Vicente Valero, Debu Tripathy, Bhuvaneswari Ramaswamy, Sara Tolaney, Nabihah Tayob, Nancy Lin, Daniel Stover, Carlos Barcenas. Clinical outcomes in early-stage TNBC according to HER2-low status [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 PO3-03-05.

Impact of body mass index on pathological response after neoadjuvant chemotherapy: results from the I-SPY 2 trial

PurposeIncreased body mass index (BMI) has been associated with poor outcomes in women with breast cancer. We evaluated the association between BMI and pathological complete response (pCR) in the I-SPY 2 trial.Methods978 patients enrolled in the I-SPY 2 trial 3/2010–11/2016 and had a recorded baseline BMI prior to treatment were included in the analysis. Tumor subtypes were defined by hormone receptor and HER2 status. Pretreatment BMI was categorized as obese (BMI ≥ 30 kg/m2), overweight (25 ≤ BMI < 30 kg/m2), and normal/underweight (< 25 kg/m2). pCR was defined as elimination of detectable invasive cancer in the breast and lymph nodes (ypT0/Tis and ypN0) at the time of surgery. Logistic regression analysis was used to determine associations between BMI and pCR. Event-free survival (EFS) and overall survival (OS) between different BMI categories were examined using Cox proportional hazards regression.ResultsThe median age in the study population was 49 years. pCR rates were 32.8% in normal/underweight, 31.4% in overweight, and 32.5% in obese patients. In univariable analysis, there was no significant difference in pCR with BMI. In multivariable analysis adjusted for race/ethnicity, age, menopausal status, breast cancer subtype, and clinical stage, there was no significant difference in pCR after neoadjuvant chemotherapy for obese compared with normal/underweight patients (OR = 1.1, 95% CI 0.68–1.63, P = 0.83), and for overweight compared with normal/underweight (OR = 1, 95% CI 0.64–1.47, P = 0.88). We tested for potential interaction between BMI and breast cancer subtype; however, the interaction was not significant in the multivariable model (P = 0.09). Multivariate Cox regression showed there was no difference in EFS (P = 0.81) or OS (P = 0.52) between obese, overweight, and normal/underweight breast cancer patients with a median follow-up time of 3.8 years.ConclusionWe found no difference in pCR rates by BMI with actual body weight-based neoadjuvant chemotherapy in this biologically high-risk breast cancer population in the I-SPY2 trial.

Abstract PD1-06: Black patients with triple negative breast cancer (TNBC) have enriched stromal tumor infiltrating lymphocytes (sTILs) and receive preferential benefit from neoadjuvant immunotherapy

Abstract Introduction TNBC is overrepresented in Black women, and Black patients with TNBC have worse clinical outcomes compared to non-Black patients. This disparity likely results from racial differences in clinical, biological, and demographic features of TNBC and social determinants of health. Neoadjuvant chemoimmunotherapy is current standard of care for high-risk TNBC. However, Black patients have been poorly represented in immunotherapy TNBC trials, making it difficult to assess comparative efficacy of immunotherapy in Black patients. Methods We utilized two TNBC neoadjuvant trials to assess racial differences in the tumor immune microenvironment composition and evaluate impact of race on response to chemotherapy vs chemoimmunotherapy. NeoSTOP trial (NCT02413320) randomized 100 stage I-III TNBC patients to receive neoadjuvant carboplatin/paclitaxel + doxorubicin/cyclophosphamide (CbP+AC) or carboplatin/docetaxel (CbD). NeoPACT trial (NCT03639948) enrolled 120 patients with stage I-III TNBC who received neoadjuvant CbD + pembrolizumab (CbD+P). sTILs were centrally quantified, and RNA extracted from pretreatment tissue was subjected to next-generation sequencing. Relative leukocyte fractions were computed by CIBERSORTx. Factors were tested as predictors of pathologic complete response (pCR) using logistic regression analysis. Event-free survival (EFS) was estimated by the Kaplan-Meier method and compared between groups by log-rank test, followed by Cox regression analysis. Results The study population includes 197 patients with known race, sTILs, and gene expression data (84 patients from NeoSTOP, 113 from NeoPACT). 15/84 (18%) patients in NeoSTOP and 20/113 (18%) patients in NeoPACT self-reported Black race. There was no significant difference in age, T or N stage, or germline BRCA1/2 mutation status by race in either study. Black patients had significantly higher sTILs than non-Black patients (median 40% vs 15%, P=0.048) and were more likely to have ≥20% sTILs than non-Black patients (66% vs 44%, P=0.026). There was no significant difference in pCR by race in NeoSTOP (OR=0.60, 95% CI 0.19-1.84, P=0.37; pCR 47% for Black vs 59% for non-Black). In contrast, in NeoPACT, Black patients had a significantly higher pCR compared to non-Black patients (OR=3.27, 95% CI 1.01-10.64, P=0.049; pCR 79% for Black vs 53% for non-Black). In NeoSTOP, EFS was similar for Black and non-Black patients (3-year EFS 92% and 94%, respectively, HR=0.88, 95% CI 0.11-7.28, P=0.90). In NeoPACT, EFS was numerically higher in Black vs non-Black patients (3-year EFS 93% and 81%, respectively, HR=0.43, 95% CI 0.05-3.36, P=0.40); NeoPACT survival follow-up is ongoing at the time of this report. On CIBERSORTx analysis, Black patients had relative depletion of immunosuppressive pro-tumorigenic M2 macrophages (P=0.005) and CD4+ memory resting T cells (P=0.021) compared to non-Black patients. Conclusions Compared to non-Black patients, Black patients with TNBC are more likely to have immune-enriched tumors with lower relative abundance of immunosuppressive leukocytes. These findings suggest potential for higher relative magnitude of benefit from checkpoint inhibitor therapy in Black compared to non-Black patients. Supporting this biological hypothesis, we noted that Black and non-Black patients had equivalent rates of pCR with neoadjuvant chemotherapy; however, pCR rate among Black patients was significantly higher than in non-Black patients when treated with neoadjuvant chemoimmunotherapy. These findings should be confirmed in other studies and can optimize utilization of neoadjuvant chemoimmunotherapy. Our findings also underscore the importance of efforts to address disparity in access and use of immunotherapy in Black patients. Citation Format: Shane R. Stecklein, Rachel Yoder, Roberto Salgado, Joshua M. Staley, Anne O’Dea, Lauren Nye, Manana Elia, Deepti Satelli, Gregory Crane, Richard McKittrick, Andrew K. Godwin, Qamar Khan, Priyanka Sharma. Black patients with triple negative breast cancer (TNBC) have enriched stromal tumor infiltrating lymphocytes (sTILs) and receive preferential benefit from neoadjuvant immunotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD1-06.

P701: COVID-19 IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN TREATMENT-FREE REMISSION: DISEASE SEVERITY AND IMPACT ON TFR STATUS

Background: Severe SARS-CoV-2 infections associated with high mortality rates are reported in a higher percentage of patients (pts) with hematologic malignancies compared to general population. In chronic myeloid leukemia (CML), pts with uncontrolled disease have a higher mortality risk. The impact of SARS-CoV-2 infection on CML pts in treatment-free remission (TFR) has not been studied so far. In particular, as immune control of residual disease may be important for TFR, the concern is that the infection could induce loss of TFR. Aims: To evaluate the outcome of SARS-CoV-2 infection in CML pts in TFR and assess any impact on maintenance of TFR. Methods: From March 2020 to December 2021, the CANDID study organized by the international CML Foundation has collected data on COVID-19 positive CML pts worldwide. Details on the registry were presented recently (Pagano ASH 2021). For this sub-analysis on pts in TFR additional information were collected including; molecular remission status (BCR::ABL1 ratios) before, during and after SARS-CoV-2 infection covering at least 6 months. For molecular analyses, BCR::ABL1 ratios were classified according to Cross et al (Leukemia 2015). In addition, ratios of 0% without indication of sensitivity were allocated as MR4 i.e. 0.01%IS. PCR outlier results were identified using the ROUT method by nonlinear regression with a maximum false discovery rate (FDR) of 1% (Motulsky et al 2006). Time to molecular relapse (MR) was measured from the date of COVID-19 diagnosis to the date of MR defined as loss of major molecular remission (MMR, BCR::ABL1 >0.1%IS) or the date of last molecular test. Molecular relapse-free survival (MRFS) and overall survival (OS) were estimated with the Kaplan-Meier method. The statistical difference between groups was performed using log-rank test. Results: By December 2021, 1050 COVID-19 positive CML pts were registered. 95 pts were in TFR at the time point of SARS-CoV-2 infection of which 89 (93.68%) recovered and 6 deceased (6.32%). Median age of TFR pts was 57 years, male were 51 (53.68%). Median time from CML diagnosis to reporting date was 13 years (range 3.7-27.0 years). TFR duration was 2.83 years in median (range 0.5 months – 10.1 years) including 19 pts with a duration < 1 year. From the 89 recovered TFR pts, 74 pts completed the 6-month follow up (83%), a further 6 pts with molecular follow-up of 3-5 months after COVID-19 diagnosis were still in TFR, 9 pts were lost to follow-up. Of 74 pts with complete reports, 69 pts remained in TFR (93%) and 5 pts lost TFR. For 71 pts, PCR results were obtained before, during and after infection. With the ROUT method 10 pts demonstrated outlier PCR tests, 61 pts demonstrated stable PCR results. There was no statistically significant difference in PCR results before and during/after infection (p>0.2). MRFS for these 71 pts 15 months after COVID-19 diagnosis was 86%. Probability of TFR loss was higher in pts with a TFR duration < 6 months compared to pts with TFR duration >6 months (27% vs 10%, Fig 1A). Additionally, there were no statistically differences in hospitalization rate (16% vs 23%, p=0.12) and severity of COVID-19 symptoms (12.6% vs 12%, p=0.87) comparing TFR and TKI treated pts. OS of COVID-19 positive TFR pts did not differ from COVID-19 positive pts on TKI therapy (HR 1.1, CI 0.47-2.54) (Fig 1B). Image:Summary/Conclusion: In this sub-analysis of the CANDID study, CML pts in TFR had similar severity and survival to CML pts who were on TKI therapy and there was no evidence of an increased risk of TFR loss after SARS-CoV-2 infection.

Lack of racial differences in clinical outcomes of breast cancer patients receiving neoadjuvant chemotherapy: a single academic center study.

To examine the association between race and clinical outcomes (pathological complete response [pCR]; recurrence-free survival [RFS], and overall survival [OS]) in patients diagnosed with triple-negative (TNBC) or HER2-positive breast cancer treated with neoadjuvant chemotherapy (NAC). Patients who self-identified as non-Hispanic white (NHW) or non-Hispanic Black (NHB) and were diagnosed with Stage I-III TNBC (n = 171 including 124 NHW and 47 NHB) and HER2-positive (n = 161 including 136 NHW and 25 NHB) breast cancer who received NAC from 2000 to 2018 at Roswell Park Comprehensive Cancer Center were included. Associations of race with pCR and survival outcomes were evaluated using logistic and Cox regression models, respectively. There was no statistically significant difference in pCR between NHB and NHW patients with TNBC (31.9 vs 29.8%; OR: 1.11, 95% CI 0.54-2.29) or HER2-positive breast cancer (36.0 vs 39.7%; OR: 0.87, 95% CI 0.36-3.11). After controlling for potential confounders, including age, stage, treatment regimens, insurance status, and comorbidities, no statistically significant difference in OS or RFS was observed between NHB and NHW patients within either subtype. TNBC or HER2-positive breast cancer patients treated at a single academic center in Buffalo, NY, showed similar outcomes independent of patients' race. Given the known genetic diversity of African American ancestry in the US, further studies investigating the interplay between race, geography, and clinical outcomes are warranted.

P-OGC24 Comparison of the histopathological regression after neoadjuvant FLOT versus ECX in resectable gastroesophageal adenocarcinoma

Abstract Background Neoadjuvant chemotherapy is a key component in the treatment of resectable oesophagogastric cancer (OGC). Histopathological tumour regression is associated with a prognostic benefit in OGC. There is increased usage of the FLOT regimen as part of neoadjuvant chemotherapy (NAC) for these tumours. The initial phase 2 trial demonstrated complete pathological response (pCR) in 15% for FLOT versus 6% for ECX but there is no data outside a trial setting. The aim of this study was to evaluate the differences in pCR and the extent of downstaging between patients receiving FLOT versus ECX in the neoadjuvant setting. Methods Consecutive patients treated for OGC in a single, high-volume UK centre between 2018 and 2021 were identified from a contemporaneously maintained database. Patients underwent 3 cycles of ECX or 4 cycles of FLOT as part of NAC. Histopathological tumour regression was assessed by the Mandard classification. A comparison of T- and N stage migration between FLOT and ECX was performed. Major pCR was defined as TRG 1-2 based on the Mandard classification. Results The study included 162 patients. 6/84 (7.1%) patients receiving ECX and 5/78 (6.4%) patients receiving FLOT achieved a pCR (p = 0.853). 11/84 (13.1%) patients in the ECX group and 12/78 (15.4%) patients in the FLOT group achieved a major pCR (p = 0.677). With regards to stage migration by T-stage, 36 (42.9%) patients were downstaged and 6 patients (7.1%) were upstaged with ECX. Amongst FLOT patients, 42 (53.8%) were downstaged and 8 (10.3%) upstaged (p = 0.189). When comparing N-stage, 29 (34.5%) patients achieved downstaging and 28 (33.3%) were upstaged with ECX. 30 (38.5%) patients were downstaged and 20 (25.6%) were upstaged with FLOT (0.563). Conclusions There was no significant difference in pCR and stage migration rates between patients receiving neoadjuvant ECX and FLOT. pCR rates were lower than previously reported, and it is unclear if the difference in prognosis will translate comparable outcomes between patients receiving ECX versus FLOT.

Abstract PS4-22: Prevalence of HER2-low and HER2-zero subgroups and correlation with response to neoadjuvant chemotherapy (NACT) in patients with HER2-negative breast cancer

Abstract INTRODUCTION Current definition of HER2-positive BC follows ASCO/CAP guidelines using immunohistochemistry (IHC) and/or in situ hybridization (ISH)-based techniques. However, HER2 expression can be variable in cells that lack ERBB2 amplification. For example, HER2-negative tumors can express some level of HER2 protein by IHC (i.e. 1+ or 2+ and a negative ISH result) and are identified as HER2-low. Others have no expression and are considered HER2-zero. Innovative therapies have shown promising activity in patients in HER2-low BC. The aim of this study is to evaluate the association of HER2-low and HER2-zero status with response to NACT in HER2-negative BC. METHODS Retrospective cohort of patients with HER2-negative BC treated with NACT in four institutions in Brazil. Protocols of diagnosis, treatment and follow-up were standardized and based on international guidelines. Tumors with HER2 IHC score 0 were classified as HER2-zero whereas tumors with HER2 score 1+ and those with HER2 score 2+ with FISH-negative were classified as HER2-low. Patients were treated with anthracycline- and taxane- based chemotherapy. The following clinicopathological data were evaluated, when available: age, ER, Ki67, tumor size, lymph node (LN) status and response to NACT according to pCR status and residual cancer burden (RCB) index. Primary objective was to evaluate the prevalences and compare pCR rates among HER2-zero and HER2-low cases. Secondary objectives were to perform the same comparison within the HR-positive (HR+) and HR-negative subgroups. Pearsons chi squared tests were performed and a p value of &amp;lt;0.05 was considered statistically significant. RESULTS 331 patients were included in this analysis. 63% were HR+and 37% were TNBC. 50% were HER2-zero and 50% HER-low (36% HER2 IHC 1+ and 14% HER2 IHC 2+/FISH-negative). Median age, initial tumor size, clinical LN status and Ki67 expression were similar among HER2-zero and HER2-low subgroups. In HR+ tumors, 42% (86/207) were HER2-zero and 58% (121/207) were HER2-low. In TNBC, 63% (78/124) were HER2-zero and 37% (46/124) were HER2-low (p&amp;lt;0.001, Pearsons chi squared test). The pCR rate was 26% (85/331) in the entire cohort. As expected, there was a higher rate of pCR in TNBC vs HR+ (50% vs 11%, p&amp;lt;0.001). We found a statistically significant difference in the pCR rates when comparing the HER2-zero versus HER2-low subgroups (31% vs 20%, p=0.03). However, this difference is mostly related to an imbalance between groups (HER2-zero subgroups had a higher proportion of TNBC). Among HR+ tumors, there was no difference in the pCR rates between HER2-zero and HER2-low subgroups (8% vs 13%, p=0.35). In TNBC, we identified an interesting but non-statistically significant difference in pCR in HER2-zero vs. HER2-low tumors (56% vs. 39%, p=0.09). In the TNBC cohort we identified a non-statistically significant difference in RCB 0-I in HER2-zero vs. HER2-low tumors (p=0.06). With a 30 month median follow-up, PFS and OS data are immature. CONCLUSION The distribution of HER2-zero and HER2-low cases is different in HR+ and TNBC. HER2-low is more frequent in HR+ and HER2-zero in TNBC. We identified a higher pCR rate in HER2-zero compared to HER2-low tumors, even though this difference is associated with an imbalance between the two groups. Still, we identified a trend to higher pCR rate in HER2-zero compared to HER2-low tumors even within the TNBC subgroup. Identification of HER2-low and HER2-zero tumors may have clinical implications that should be further explored. Citation Format: Tomas Reinert, Guilherme Parisotto Sartori, Alessandra AB Souza, Rodrigo Pellegrini, Mahira L Rosa, Nathalia Rossatto, Guilherme P Coelho, Isnard E Litvin, Felipe Zerwes, Eduardo Millen, Francisco P Cavalcante, Antonio L Frasson, Marcia S Graudenz, Carlos H Barrios. Prevalence of HER2-low and HER2-zero subgroups and correlation with response to neoadjuvant chemotherapy (NACT) in patients with HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-22.

Abstract PS6-05: Impact of body mass index on pathological complete response after neoadjuvant chemotherapy: Results from the I-SPY 2 trial

Abstract Purpose: Increased body mass index (BMI) is a risk factor for breast cancer and has been associated with poor outcomes in both premenopausal and postmenopausal breast cancer patients. Several retrospective studies have demonstrated higher BMI to be associated with inferior pathological complete response (pCR) to neoadjuvant chemotherapy, yet it remains unclear if this difference is related to chemotherapy underdosing among obese breast cancer patients. We evaluated the association between BMI and response to neoadjuvant chemotherapy (defined by pCR) in the I-SPY 2 trial, an adaptive clinical trial platform enrolling biologically high-risk breast cancer patients (triple negative, human epidermal growth factor receptor 2 (HER2) positive and MammaPrint high-risk) that utilizes standard neoadjuvant therapy regimens with treatment based on actual body weight. Patients and Methods: From 3/2010 to 11/2016, 989 patients were enrolled in the I-SPY 2 trial, 978 had a recorded baseline BMI prior to treatment and were included in the analysis. Tumor subtypes were defined by hormone receptor and HER2 status. Pretreatment BMI was categorized as obese (BMI&amp;gt;=30 kg/m2), overweight (25=&amp;lt;BMI&amp;lt;30 kg/m2), and normal or underweight (&amp;lt;25 kg/m2) based on World Health Organization criteria. pCR was defined as elimination of detectable invasive cancer in the breast and lymph nodes (ypT0/Tis and ypN0) at the time of surgery. Logistic regression analysis was used to determine associations between BMI and pCR, and we reported odds ratios (OR) and 95% confidence intervals (CI). Event-free survival (EFS) and overall survival (OS) between different BMI categories were examined using Cox proportional hazards regression. Results: The median age in our study population was 49 years. 35% of patients were normal/underweight, 32% overweight, and 33% obese. Black patients were more likely to be obese (P&amp;lt;0.0001). pCR rates differed significantly by tumor subtype (P&amp;lt;=0.0001) and tumor stage (P=0.0009). pCR rates were 32.8% in normal/underweight, 31.4% in overweight, and 32.5% in obese patients. In univariable analysis, there was no significant difference in pCR with BMI. In multivariate analysis adjusted for race/ethnicity, age, menopausal status, breast cancer subtype, and clinical stage, there was no significant difference in pCR to neoadjuvant chemotherapy for obese compared with normal/underweight patients (OR=1.1, 95%CI: 0.68-1.63, p=0.83), and for overweight compared with normal/underweight (OR=1, 95%CI: 0.64-1.47, p=0.88). We tested for potential interaction between BMI and breast cancer subtype, however, the interaction was not significant in the multivariate model (P=0.09) (Table 1). Multivariate Cox regression showed there was no difference in EFS (p=0.81) or OS (p=0.52) between obese, overweight and normal/underweight breast cancer patients with a median follow-up time of 4.0 years. Conclusions: There was no difference in pCR rates by BMI with actual body weight based neoadjuvant chemotherapy in this biologically high-risk breast cancer population. In contrast, breast cancer subtype and stage showed predictive value for pCR in this high-risk operable breast cancer population receiving neoadjuvant chemotherapy in the I-SPY 2 clinical trial. Table 1: pCR rate of different BMI categories by breast cancer subtypes.Breast Cancer SubtypepCRNormal/underweight Frequency (%)OverweightFrequency (%)ObeseFrequency (%)P-valueHR+/HER2+No39 (61.9)27 (61.4)32 (66.7)0.83Yes24 (38.1)17 (38.6)16 (33.3)HR+/HER2-No105 (80.8)116 (89.2)93 (78.8)0.06Yes25 (19.2)14 (10.8)25 (21.2)HR-/HER2+No7 (25.0)11 (35.5)15 (51.7)0.11Yes21 (75.0)20 (64.5)14 (48.3)HR-/HER2-No83 (65.4)58 (55.8)76 (60.8)0.33Yes44 (34.7)46 (44.2)49 (39.2)(HR: hormone receptor, HER2: human epidermal growth factor receptor 2) Citation Format: Haiyun Wang, Douglas Yee, David Potter, Patricia Jewett, Christina Yau, Heather Beckwith, Allison Watson, Nicholas G O'Grady, Amy Wilson, Susie Brain, I-SPY 2 TRIAL Consortium, Anne Blaes. Impact of body mass index on pathological complete response after neoadjuvant chemotherapy: Results from the I-SPY 2 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-05.

A machine learning model that classifies breast cancer pathologic complete response on MRI post-neoadjuvant chemotherapy

BackgroundFor breast cancer patients undergoing neoadjuvant chemotherapy (NAC), pathologic complete response (pCR; no invasive or in situ) cannot be assessed non-invasively so all patients undergo surgery. The aim of our study was to develop and validate a radiomics classifier that classifies breast cancer pCR post-NAC on MRI prior to surgery.MethodsThis retrospective study included women treated with NAC for breast cancer from 2014 to 2016 with (1) pre- and post-NAC breast MRI and (2) post-NAC surgical pathology report assessing response. Automated radiomics analysis of pre- and post-NAC breast MRI involved image segmentation, radiomics feature extraction, feature pre-filtering, and classifier building through recursive feature elimination random forest (RFE-RF) machine learning. The RFE-RF classifier was trained with nested five-fold cross-validation using (a) radiomics only (model 1) and (b) radiomics and molecular subtype (model 2). Class imbalance was addressed using the synthetic minority oversampling technique.ResultsTwo hundred seventy-three women with 278 invasive breast cancers were included; the training set consisted of 222 cancers (61 pCR, 161 no-pCR; mean age 51.8 years, SD 11.8), and the independent test set consisted of 56 cancers (13 pCR, 43 no-pCR; mean age 51.3 years, SD 11.8). There was no significant difference in pCR or molecular subtype between the training and test sets. Model 1 achieved a cross-validation AUROC of 0.72 (95% CI 0.64, 0.79) and a similarly accurate (P = 0.1) AUROC of 0.83 (95% CI 0.71, 0.94) in both the training and test sets. Model 2 achieved a cross-validation AUROC of 0.80 (95% CI 0.72, 0.87) and a similar (P = 0.9) AUROC of 0.78 (95% CI 0.62, 0.94) in both the training and test sets.ConclusionsThis study validated a radiomics classifier combining radiomics with molecular subtypes that accurately classifies pCR on MRI post-NAC.

Abstract OT1-01-06: A pilot study utilizing a HER2 directed dendritic cell vaccine during neoadjuvant therapy of HER2+ breast cancer

Abstract Background: During the natural progression of early breast cancer, it has been demonstrated that the protective host immune response against HER2 is lost early on. Using a type 1 dendritic cell (DC1) vaccine loaded with HER2 peptides has been shown to be effective in restoring anti HER2 immune responsiveness and can lead to regression of very early non-invasive breast cancers. Prior investigations conducted by our group has suggested DC vaccines may sensitize cancers to subsequent systemic chemotherapy, and the Geparnuevo trial also suggested a prechemotherapy dosing with checkpoint therapy may improve pathologic complete response (pCR) rates in TNBC. We launched a pilot study to demonstrate safety, feasibility, and preliminary efficacy of administering the DC1 HER2 vaccine for 3 weeks prior to the initiation of neoadjuvant systemic therapy for stage II-III ER-HER2+ breast cancer. Methods: This single site study is a pilot design with a safety run in phase (n = 12) followed by an expansion cohort of 18 patients. Patients with stage II-III ER-HER2+ breast cancer who are eligible to receive neoadjuvant HER2 based chemotherapy (TCHP) can enroll. The safety run in evaluates two schedules of DC1 vaccination (ARM A = once weekly x 3 weeks and ARM B = twice weekly x 3 weeks) and will enroll six patients in each arm. After the first 3 weeks of DC1 neoadjuvant chemotherapy will be administered using standard docetaxel, carboplatin, trastuzumab, and pertuzumab given intravenously once every 3 weeks for 6 cycles. Booster vaccines will be given at weeks 25, 56, 80, and 104 and immune monitoring will be performed at these timepoints. The safety run in will evaluate safety using CTCAE 4.03 criteria along with the immunogenicity of each arm measured by ELISPOT. The arm with the best immune response at 3 weeks will be selected to proceed forward during the expansion cohort using an endpoint of pCR. Secondary endpoints will be recurrence free survival rate at 3 years and immune response. The pilot design is hypothesis generating but is likely able to detect a significant difference in pCR if the true rate is 75% assuming a historical rate of 55%. Accrual to the safety run in phase is complete and the expansion phase is underway using the twice weekly vaccination schedule. Citation Format: Hatem Soliman, Deanna Hogue, Hyo Han, Hung Khong, Ricardo Costa, Avan Armaghani, Axia Soyano Muller, Nazanin Khakpour, Marie C Lee, John Kiluk, Brian Czerniecki. A pilot study utilizing a HER2 directed dendritic cell vaccine during neoadjuvant therapy of HER2+ breast cancer [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 OT1-01-06.

Induction Chemotherapy for Locally Advanced Esophageal Cancer.

Concurrent chemoradiotherapy followed by surgery is the standard treatment for locally advanced esophageal cancer (EC), and the role of induction chemotherapy (IC) remains unclear. We aimed to study if the addition of IC to standard treatment increases the rate of pathologic complete response (pCR). We assembled a retrospective analysis of patients (pts) diagnosed with locally advanced EC and treated with preoperative chemoradiotherapy followed by esophagectomy (CRT+S), preceded or not by IC, between 2009 and 2017. Patients' characteristics, tumor variables, and treatment outcomes were evaluated. The Kaplan-Meier method was used to estimate overall survival and the Cox proportional hazard model to evaluate prognostic factors. One hundred and three patients were studied, with a median age of 62years (range 37-84). Seventy-five patients (73%) were male, 67 (65%) had squamous cell carcinoma, and 31 (30%) had adenocarcinoma. Forty-three patients (41.7%) received IC followed by CRT+S (IC+CRT+S). The most frequent IC consisted of paclitaxel and platinum chemotherapy (90%), and the median number of cycles was 2. All patients received CRT+S. Concurrent chemotherapy was a combination of paclitaxel and platinum in 94 patients (91%). There was no statistically significant difference in pCR between the IC group and the standard CRT+S group. The pCR was 41.9% and 46.7% in the IC+CRT+S and CRT+S groups (p = 0.628), respectively. In the multivariate analysis, pCR was an independent prognostic factor for time to treatment failure (TTF) (HR 0.35, p = 0.021), but not for overall survival (OS) (p = 0.863). The factor that significantly affected OS in the multivariate analysis was positive lymph node (HR 5.9, 95%, p = 0.026). Our data suggest that the addition of IC to standard CRT + S does not increase the pCR rate in locally advanced EC. No difference in OS was observed between pts. that received or not IC. Regardless of the treatment received, pts. achieving a pCR presented improved TTF.

Intrinsic subtypes of HER2-positive breast cancer and their associations with pathologic complete response (pCR) and outcomes: Findings from NSABP B-41, a randomized neoadjuvant trial.

580Background: NSABP B-41, randomly assigned 529 patients with HER2 positive breast cancer to receive neoadjuvant trastuzumab, lapatinib, or the combination, with weekly paclitaxel following doxorubicin and cyclophosphamide x 4. No significant difference in pCR was found among three arms (Robidoux 2013), but overall survival was significantly increased for patients who obtained a pCR (Robidoux 2016). This study evaluated outcomes in B-41 based on intrinsic subtype. Methods: H&E slides were reviewed by study pathologist for areas of invasive carcinoma having > 10% tumor cells. RNA was isolated and hybridized to the “RUO-PAM50” CodeSet (NanoString Technologies). Intrinsic PAM50 subtype was determined for each sample. Contingence-table analyses were used to compare pCR breast and nodes (ypT0/is ypN0) among intrinsic subtypes and Kaplan-Meier estimates and Cox models were used to compare event-free survival and overall survival among subtypes. Results: Core biopsy samples from 276 patients, prior to therapy, ...

Prospective randomized trial of neoadjuvant chemotherapy during the 'wait period' following preoperative chemoradiotherapy for rectal cancer: results of the WAIT trial.

The aim was to determine whether the addition of additional cycles of chemotherapy during the 'wait period' following neoadjuvant chemoradiotherapy for rectal cancer improves the pathological complete response (pCR) rate. Rectal cancer patients were randomly allocated either to a standard 10week wait period before surgery (standard chemoradiotherapy, SCRT) or to receive three cycles of fluorouracil based chemotherapy following chemoradiotherapy during a similar 10week wait (extended chemoradiotherapy, XCRT). The primary end-point was pCR as determined by blinded pathological assessment. Forty-nine patients were randomized (SCRTn=24, XCRTn=25). pCR occurred in 10 patients overall but there was no significant difference in pCR between the groups (SCRTn=6, XCRTn=4, P=0.49). The addition of three cycles of 5-fluorouracil/leucovorin in a 10week wait period after conventional chemoradiotherapy seems to result in similar pCR rates in patients with locally advanced rectal cancer based on this small randomized trial.

Abstract P5-16-05: MINT trial yields MammaPrint High1/High2 risk classes associated with significant differences in pCR and receptor subtype

Abstract Background: Previous clinical trials have validated that the 70-gene signature MammaPrintTM provides prognostic and predictive information for early stage breast cancer patients and can identify low risk patients who may safely avoid adjuvant chemotherapy. Additionally, the neo-adjuvant I-SPY 1&amp;2 TRIALs demonstrated that further stratification of patients into MammaPrint High 1 (MP1) and MammaPrint High 2 (MP2) risk groups may help predict chemo-sensitivity. There were significant differences in pathological complete response (pCR) rates for early stage, locally advanced breast cancer patients who were not HR+HER2- MammaPrint Low Risk. Specifically, the PARP inhibitor veliparib in combination with carboplatin recently graduated the I-SPY 2 phase 2 screening trial, having met the 85% predictive probability criterion with a triple-negative breast cancer signature, which was the subset recommended for this regimen's subsequent development. Given these data, we wanted to determine whether the Multi Institutional Neo Adjuvant Therapy MammaPrint Project (MINT) patient population confirmed the MP1/MP2 risk stratification, clarify if there is an associated receptor subtype for MP1/MP2 risk classes, and conclude if the stratification correlates to a significant difference in pCR. Methods: Array data from pre-treatment samples were obtained from 180 patients classified as MammaPrint High Risk, subtyped by IHC and treated with neo-adjuvant chemotherapy according to protocol. Response was measured by centrally assessed residual cancer burden pursuant to guidelines. Patients were then further stratified based on the MammaPrint Index per their classification threshold between MP1/MP2. Fisher's exact test was used to assess significance of association with pCR overall and within hormone receptor (HR) and HER2 subtypes. Results: MP1 vs MP2 risk classes yielded subsets with significant (p=0.007) differences in pCR. 44% (40/92) of MP2 patients achieved a pCR, compared to 24% (21/88) of MP1 patients. Next, we investigated whether the MP1 and MP2 risk classes were associated with receptor subtype. MP1 demonstrated a significant association and MP2 near significance. 32% (21/66) of triple-negative patients were classified as MP2 vs only 3% (2/66) MP1. Similarly, in the overall population, 28% (51/180) HR+HER2- are classified as MP1 vs 4% (8/180) MP2. Results in the pCR population were reflective of these subtype trends. 63% (58/92) of MP2 patients were classified triple-negative, of which nearly one quarter (21/92) had a measured pCR, whereas 58% (51/88) of MP1 patients were HR+HER2- with 3% (3/88) achieving pCR (Table1). Conclusion: This analysis in the MINT patient population supports previously published data and suggests that the MammaPrint High 1/2 risk classification may help predict chemo-sensitivity. Given the statistical significance of these data, we are currently investigating the biological mechanisms distinguishing the MP1/MP2 subgroups that may account for its use as a specific biomarker of response to chemotherapy treatment in future trials. Table 1.MP1MP2HER2+HER2-HER2+HER2-HR+HR-HR+HR-HR+HR-HR+HR-793241322185486456371514518818858Row#1= pCR, #2= RD, #3= Total Citation Format: Blumencranz LE, Shivers SC, Untch S, Treece TD, Yoder E, Blumencranz PW, Cox CE. MINT trial yields MammaPrint High1/High2 risk classes associated with significant differences in pCR and receptor subtype [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-05.

Abstract P3-07-03: PIK3CA mutations predict resistance to trastuzumab/pertuzumab and nab-paclitaxel in primary HER2-positive breast cancer – Massive parallel sequencing analysis of 293 pretherapeutic core biopsies of the GeparSepto study

Abstract Background: Phosphatidylinositol 3-kinase mutations (PIK3CA) are common in breast cancer (BC). Mutations are predominantly found in hot-spots located in the helical and kinase domains (exons 9 and 20). We recently demonstrated that PIK3CA mutations predict lower pathological complete response (pCR) to double blockade with trastuzumab/lapatinib in HER2+ve primary BC. Methods: We evaluated PIK3CA mutations in 293/403 HER2+ve tumors of participants of the neoadjuvant GeparSepto (G7) study (Untch et al. SABCS 2014). The G7 study investigated the effect of exchanging paclitaxel for nab-paclitaxel prior to EC. All patients received trastuzumab and pertuzumab. The G7 study showed a significantly higher pCR rate in patients receiving nab-paclitaxel. HER2, hormone receptors (HR), Ki67 and tumor infiltrating lymphocytes (TILs) were centrally assessed prior to randomization. PIK3CA mutations in exons 9 and 20 were evaluated in formalin-fixed, paraffin embedded core biopsies taken before therapy using deep targeted massive parallel sequencing with a minimum coverage of 500 and a mean coverage of 6520 and 6346 per amplicon, (exon9 and exon 20). Only non-synonymous mutations in the coding region that were called at variant allele frequency ≥10% were taken into consideration. Only cases with a tumor cell content of ≥20% were included. Results: In the G7 study, 396 patients with HER2+ve BC have been randomized from 06/2012 to 01/2014 and started treatment. From these 293 could be sequenced. Median age in the analyzed cohort was 49 years (range 22-75); most tumors were cT1-2 (89.9%); cN0 (54.4%); ductal invasive (88.7%), grade 3 (53.9%), HR+ve (69.6%), Ki67&amp;gt;20% (69.3%), LPBC-negative (83.2%). Overall, 22.2% of the tumors were found to have a PIK3CA mutation, 20.1% in HR+ve and 27.0% in HR-ve. Overall, the pCR rate was significantly lower in the PIK3CA mutant tumors compared to the wild type (wt) group (47.7% vs. 66.7%; p=0.009). This effect was seen both in the HR+ve (43.9% vs. 61.3%; p=0.052) and the HR-ve population (54.2% vs. 80.0%; p=0.029). There was also a significant difference in pCR according to PIK3CA mutation status dependant on the taxane. In the nab-paclitaxel group, pCR rates were significantly lower in patients with PIK3CA mutations compared to those without PIK3CA mutations (38.7% vs. 72.0%; p=0.001), whereas in the paclitaxel group, there was no significant difference between patients with and without a PIK3CA mutation (55.9% vs. 60.9%; p=0.690). The respective interaction could be demonstrated in univariate (p=0.039) as well as multivariate regression analysis (p=0.010) after adjusting for known baseline factors. Conclusion: Patients with PIK3CA mutant HER2+ve BC have a significantly lower pCR rate compared to patients with wt tumors. In contrast to the results with double anti-HER2 blockade consisting of trastuzumab/lapatinib, the effect was evident irrespective of the HR status. In addition, PIK3CA mutation status was significantly associated with higher pCR following nab-paclitaxel. The project has partly been funded within the EU-FP7 project RESPONSIFY No 278659 and the German Cancer Consortium (DKTK). Citation Format: Loibl S, Budczies J, Weichert W, Furlanetto J, Stenzinger A, Pfarr N, von Minckwitz G, Jackisch C, Schneeweiss A, Fasching P, Schmatloch S, Aktas B, Nekljudova V, Weber K, Untch M, Denkert C. PIK3CA mutations predict resistance to trastuzumab/pertuzumab and nab-paclitaxel in primary HER2-positive breast cancer – Massive parallel sequencing analysis of 293 pretherapeutic core biopsies of the GeparSepto study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-03.

Role of KRAS mutation as predictor of pathologic response after neoadjuvant chemoradiation therapy for rectal cancer.

Individual patient response to neoadjuvant treatment is variable and reproducible biomarkers of response are needed. The role of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) in rectal cancer remains equivocal. The aim of the current study was to evaluate the effect of KRAS mutation on outcomes following neoadjuvant chemoradiation therapy (CRT) for rectal cancer. A total of 76 stage II-III rectal cancer patients underwent preoperative CRT followed by surgery. In every patient tumor-related features and outcome results were considered for analysis and correlation with KRAS mutations. Forty-four patients (58%) obtained a downstaging after CRT, and in 7 patients (9%) a complete pathological response was found. Twenty-six (33%) mutations of KRAS were found in 26 patients. Nineteen mutations (73%) were located in codon 12, 6 in codon 13(23%) and 1 in codon 61. T-level downsizing and tumor downstaging showed no significant association with KRAS mutation status, except for mutation of codon 13(G13D). No correlation between cancer-associated mortality following CRT and surgery and KRAS mutation was observed. No correlation between pelvic recurrence and KRAS mutation was observed. KRAS mutation also failed to correlate with disease-free survival. No patients with a pCR had a local or distant failure. There appears to be no significant difference in pCR, tumor down-staging, T-downsizing or effects on cancer-associated mortality, overall survival and disease-free survival in patients with KRAS mutations except for patients with KRAS codon 13 mutations that seem to be resistant to neoadjuvant CRT and less likely to achieve a pCR.

Abstract P1-08-22: The impact of obesity on response to neoadjuvant chemotherapy in operable breast cancer patients

Abstract Background The association between obesity and response to neoadjuvant chemotherapy in breast cancer patients is not clear. We evaluated the impact of obesity on response to neoadjuvant chemotherapy in patients with operable breast cancer. Methods From May 2008 to December 2010, 104 patients were diagnosed with invasive breast cancer at Korea University Anam Hospital and received neoadjuvant chemotherapy before surgery. Patients were classified into those of normal (BMI of 18.5 to &amp;lt;25kg/m2), overweight (BMI of 25 to &amp;lt;30kg/m2), or Obese (BMI≥30kg/m2). The association between body mass index and pathologic response (pathologic complete response(pCR) and pathologic partial response(pPR)) to neoadjuvant chemotherapy was examined using logistic regression. Results Median age was 45 years. Mean BMI was 24.8 kg/m2; 53.8% had a normal BMI, 35.6% overweight, and 10.6% of patients was obese. BMI did not show a significant association with ER status, PR status, HER-2 status, lymph node involvement and neoadjuvant chemotherapy regimen. In univariate analysis, overweight and obese patients were significantly less likely to have a pCR compared with normal weight patients (odds ratio [OR] = 0.300; 95% CI, 0.115 to 0.784; p = 0.010). In multivariate analysis, ER negativity was significantly associated with a pCR and pPR to neoadjuvant chemotherapy (OR = 2.987; 95% CI, 1.128 to 7.907; p = 0.028), And there was significant difference in pCR for overweight and obese compared with normal weight patients (OR = 0.304;95% CI, 0.115 to 0.803; p = 0.016). Conclusion This study suggests that higher BMI should be considered to be a factor of worse response to neoadjuvant chemotherapy in patients with operable breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-22.

Insight or Confusion: Survival After Response-Guided Neoadjuvant Chemotherapy in Breast Cancer

In current clinical practice, the use of neoadjuvant chemotherapy for the treatment of breast cancer is well established. Once reserved for the treatment of locally advanced inoperable tumors, the neoadjuvant treatment strategy has been increasingly employed in operable breast cancer with good reason. This strategy offers a number of advantages over adjuvant therapy, with in vivo assessment of tumor response ranking among the most important. The neoadjuvant strategy has shown great potential as a platform for drug development, and this has led the US Food and Drug Administration to recently strongly consider pathologic response to neoadjuvant therapy as an end point to support accelerated drug approval in high-risk early-stage breast cancer. 1 Historical results from a series of important neoadjuvant trials have shaped our current thinking. It has been clearly established that long-term outcomes are similar whether treatment is given preoperatively or postoperatively and that a pathologic complete response (pCR) at the time of surgery is associated with a favorable outcome in all patients who achieve it. 2-4 Failure to achieve a pCR is clearly associated with worse long-term outcomes in triple-negative and human epidermal growth factor receptor 2 (HER2) –positive breast cancer, though this negative prognostic association is not observed for the majority of hormone receptor–positive breast cancers. 5-7 Rates of pCR following neoadjuvant chemotherapy in hormone responsive breast cancer are uniformly low and because these patients arguably receive their most important therapy, endocrine therapy, after chemotherapy, the focus of current neoadjuvant chemotherapy trials has shifted away from this group of patients in large part. Instead, neoadjuvant endocrine therapy strategies have been increasingly investigated for these patients and the field has moved more generally toward strategies to omit chemotherapy in hormone receptor–positive patients unlikely to derive benefit based on results of multiplex gene expression assays. In the article that accompanies this editorial, von Minckwitz et al 8 report survival outcomes after response-guided neoadjuvant chemotherapy in the German Breast Group GeparTrio study. In the German Breast Group tradition, this phase III study represents an enormous effort that tests an interesting strategy of response-guided chemotherapy treatment. More than 2,000 patients with stage II/III breast cancer were treated with an initial two cycles of docetaxel 75 mg/m 2 , doxorubicin 50 mg/m 2 , and cyclophosphamide 500 mg/m 2 on day 1 every 21 days (TAC). Patients achieving clinical response were then randomly assigned to continuing the same therapy for four or six additional cycles and nonresponders were randomly assigned to continue the same therapy or sequence to an alternate chemotherapy combination of navelbine 25 mg/m 2 days 1 and 8 and capecitabine 1,000 mg/m 2 orally twice per day on days 1 through 14 of a 21-day cycle (NX) for four cycles. Patients were accrued from 2002 to 2005 and the patient characteristics and therapies are reflective of the times. Notably, HER2 status was unknown in approximately 20% and no patient received neoadjuvant or adjuvant trastuzumab. The primary end points of the study were to compare pCR rates in early responders and clinical response in early nonresponders. The previously reported primary results showed a nonstatistically significant difference in pCR among early responders treated with TAC 6 compared with TAC 8 (21% v 23.5%; P .27) 9 and similar clinical responses were observed among early nonresponders with TAC 6 compared with TAC NX (50.5% v 51.2%; P .008 for noninferiority). 10 In the article accompanying this editorial, von Minckwitz et al 8 report on the predefined secondary end points of disease-free survival (DFS) and overall survival (OS). At a median follow-up of 62 months, DFS was significantly longer in early responders treated with TAC 8 compared with TAC 6 (hazard ratio [HR], 0.78; 95% CI, 0.62 to 0.97; P .026) and in early nonresponders treated with TAC NX compared with TAC 6 (HR, 0.59; 95% CI, 0.49 to 0.82; P .001). No significant difference in OS was observed in these two groups, though there was a trend toward improved OS in responders receiving TAC 8 compared with TAC 6 (HR, 0.76; 95% CI, 0.57 to 1.01; P .060). As the sample size was calculated to provide adequate power for the primary end point, the study is underpowered for the end points of DFS and OS. In addition, though the groups were reasonably balanced in terms of baseline characteristics, there were fewer patients with grade 3 tumors in the nonresponder group treated with TAC NX (25%) compared with TAC 6 (36%), and this difference was statistically significant. The unexpected finding, namely, that response-guided therapy influences disease-free survival only in hormone receptor– positive and not hormone receptor–negative breast cancer, rests on a secondary exploratory subgroup analysis and therefore needs to

Altered relative concentrations of high-energy phosphates in patients with uraemic cardiomyopathy measured by magnetic resonance spectroscopy

Premature sudden cardiovascular death is the commonest cause of death in end-stage renal disease (ESRD) patients and is associated with uraemic cardiomyopathy [left ventricular hypertrophy (LVH), systolic dysfunction (LVSD) or LV dilation]. High-energy phosphates (HEP), quantified using phosphorus-31 magnetic resonance spectroscopy, are reduced in patients with diabetes, heart failure and uraemia. Phosphocreatine:β adenosine triphosphate (PCr:ATP) ratio is an index of metabolic activity. We compared resting HEPs in ESRD patients and hypertensive patients (with and without LVH) who had normal renal function (LVH-only or normal myocardia). We also assessed associations of HEP levels with abnormalities of uraemic cardiomyopathy. Fifty-three ESRD and 30 hypertensive patients (18 with LVH, 12 with normal myocardia) underwent phosphorus magnetic resonance spectroscopy of their left ventricle. PCr:ATP ratios were calculated from (31)P-MR spectra obtained from long-axis views of the left ventricle. There were no significant differences in age, LV mass, chamber sizes and ejection fraction between patient groups. PCr:ATP was significantly lower in ESRD patients compared to hypertensive patients, irrespective of the presence or absence of LVH (P = 0.01). In the ESRD group, PCr:ATP was significantly lower in patients with LVSD (P = 0.05) and LV dilation (P = 0.01). LVH was not associated with significant difference in PCr:ATP. ESRD patients have lower HEP levels compared to hypertensive patients. Lower PCr:ATP ratio, indicating altered myocardial metabolic function in ESRD patients, is associated with features of uraemic cardiomyopathy.

Effect of adding gefitinib to neoadjuvant chemotherapy in estrogen receptor negative early breast cancer in a randomized phase II trial

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has shown both anti-proliferative and anti-tumoral activity in breast cancer. This study was designed to determine the effect of adding gefitinib to neoadjuvant epirubicin and cyclophosphamide (EC) on tumor response rates. Women with unilateral, primary operable, estrogen receptor negative invasive breast cancer ≥ 2 cm were eligible for inclusion. Randomized patients were to receive four cycles of neoadjuvant EC plus 12 weeks of either gefitinib (250 mg daily) or placebo. Primary endpoint was pathologic complete response (pCR), and secondary endpoints were complete response (CR) and overall objective response (OR). 181 patients were randomized. A pCR was observed in 17% (12/71) of patients treated with gefitinib and in 12% (9/73) of patients treated with placebo (4.57% difference, 95% CI -7.19 to 6.33; P = 0.44). CR was observed in 10% of patients in both the gefitinib (7/71) and the placebo group (7/73) (0.27% difference, 95% CI -9.6 to 10.2; P = 0.96). There was no significant difference in OR (5.96%; 95% CI -9.9 to 21.9; P = 0.45) between the two groups. Post hoc subgroup analysis showed a significant difference in pCR between triple negative breast cancer (TNBC) and non-TNBC tumors (P = 0.03). More patients in the gefitinib arm had hematological toxicity (P = 0.15) and discontinued treatment (9/94 vs. 2/86) because of adverse events (AE). Tumor response rates were similar in the two groups. A significantly higher pCR rate was observed post hoc in TNBC versus non-TNBC independent of treatment. More patients in the gefitinib group discontinued treatment because of AE.