Significant Difference In pCR Rate Research Articles

Role of NEDD9 expression in non-metastatic HER2-positive breast cancer.

e12645 Background: Neural Precursor Cell Expressed Developmentally Downregulated Protein 9 (NEDD9) is a member of the associated substrate family. Our previous studies demonstrated the role of NEDD9 overexpression in early tumorigenesis in HER2-positive (HER2+) breast cancer in vivo. Tissue microarray-based analysis showed a strong correlation between NEDD9 mRNA and relapse-free survival (RFS) and pathologic complete response (pCR) rate in HER2+ breast cancers. In this study, NEDD9 expression in non-metastatic HER2+ breast cancer was evaluated by tissue microarray. Methods: A total of 64 patients with non-metastatic HER2+ cancer of the breast who had received neoadjuvant chemotherapy and had sufficient pathology specimens were included in the study. NEDD9 was stained by tissue microarray, and the expression was subclassified as low, intermediate, and high based on the NEDD9 expression score. The correlations of NEDD9 expression with the clinical/biological characteristics, treatment, and treatment response were analyzed by Fisher Exact test. Results: A total of 64 patients were included in the study, with a medium follow-up duration of 4.6 years. The median age was 54, 1 patient was male, 79.3% of patients had stage 2 disease, 1 patient had inflammatory breast cancer, and 37.5% of patients had ER/PR negative disease. The most common neoadjuvant chemotherapy regimen was TCHP (82.5%), 44.4% of patients underwent lumpectomy, and 67.7% of patients underwent axillary lymph node dissection (ALND). 54% of patients achieved complete pathologic response (pCR), all patients received adjuvant anti-HER2 treatment, 85.7% received adjuvant radiotherapy, and 74.6% received adjuvant endocrine therapy. The NEDD9 expression distribution for low, intermediate, and high were 37.5%, 50.0%, and 12.5%, respectively. NEDD9-high patients had higher tumor stage and grade than NEDD9-low/ intermediate patients (p = 0.004, p= 0.041). More NEDD9-high patients underwent ALND compared to NEDD9- low/intermediate patients (p = 0.09). There is no statistically significant difference in pCR rate between NEDD9 expression groups, although numerically more NEDD9-high patients achieved pCR (75%, 56.2%, and 43.5% in NEDD9-high, intermediate, and low patients). Conclusions: In non-metastatic HER2+ breast cancer, NEDD9 expression is associated with more advanced tumor grade and stage. There is no statistically significant difference in pCR rate between groups, although more patients achieved pCR with a higher level of NEDD9 expression. The sample size limits our study. Additional study is needed to evaluate the correlation between NEDD9 expression and pCR rate following neoadjuvant chemotherapy in HER2+ breast cancer.

Real-world efficacy and adverse events of neoadjuvant immunotherapy in patients with early-stage triple-negative breast cancer: A multi-center experience.

e23293 Background: Pembrolizumab (pembro) combined with neoadjuvant chemotherapy (NAC) consisting of carboplatin- paclitaxel and doxorubicin-cyclophosphamide is the current standard of care in early-stage triple negative breast cancer (TNBC) based on KEYNOTE 522, which demonstrated improvements in pathologic complete response (pCR) to 65% but associated with high incidence of immune related adverse events (irAEs). We investigated real-world clinical outcomes and toxicity of this regimen. Methods: We conducted a retrospective, multi-center observational study among TNBC patients (pts) treated with NAC and pembro at 4 academic institutions from July 2021-December 2023. Data on clinicodemographic variables, irAEs, and clinical outcomes were collected. Multivariable logistic regressions were used to evaluate the association between demographic/clinical characteristics and pathological response while controlling for confounders. Analyses were performed in R (v4.2.3) at a significance level of ≤ 0.05. Results: 145 pts were analyzed, all females, with median age 53.5 years (IQR 43.4-62.7), 66% White and 23.4 % Black, median body mass index 28.3 kg/m2 (IQR 23-32), 55.6% stage II and 34% stage III disease. Median follow up was 12.3 months from the date of diagnosis. 94 pts (64.8%) attained pathological complete response (pCR). The median number of Pembro cycles prior to surgery was 7. Receipt of < 8 pembro cycles was associated with lower pCR rate compared to ≥ 8 cycles (37.2% vs 62.8%, p = 0.03). Pts in pCR group were younger than in non-pCR group (50.8 vs. 58.5 years, p = 0.002). The non-pCR group received lower relative dose intensity (RDI) of carboplatin (91.7% vs 96.6%, p = 0.001), paclitaxel (90% vs 92%, p = 0.03), cyclophosphamide (91% vs 96%, p = 0.04)compared to the pCR group. Median absolute eosinophil count (AEC) was higher in pCR group compared to non-pCR group (140/μl vs 110/μl). Higher baseline AEC was associated with higher pCR rate on multivariate analysis (OR 4.54, CI 2.08 - 50.0, p = 0.02) after adjusting for confounders such as age, number of pembro cycles, RDI, race and comorbidities. No other variables were predictive of pCR in multivariate analyses. 48.3% pts experienced irAE of any grade and 38% grade 3+ irAE. The most common irAEs were hypothyroidism (21.3%), transaminitis (20%), rash (17.5%), colitis (12.5%), adrenal insufficiency (10%), pneumonitis (8.8%), and infusion reactions (8.8%). No significant difference in pCR rate (57% vs 62%) and incidence of irAEs (42% vs 50%) were noted between Black and White pts respectively. Conclusions: The pCR rate in our study (64.8%) was comparable to KEYNOTE 522 but there was higher incidence of irAEs (48.3%). Higher AEC at baseline was associated with improved pathologic response to chemoimmunotherapy. More real world studies are needed to confirm the high incidence of irAEs that was observed in our study.

Abstract PO4-25-03: Comprehensive immune profiling reveals factors associated with neoadjuvant chemotherapy response in triple negative breast cancer

Abstract Background: KEYNOTE-522 has resulted in FDA approval of the immune checkpoint blocker pembrolizumab with neoadjuvant chemotherapy for patients with high-risk triple negative breast cancer (TNBC), given the remarkable improvement in pCR rate to 65% along with improvement in event free survival, while with chemotherapy alone, the pCR rate is 40-50%. Unfortunately, use of pembrolizumab is associated with several immune related adverse events (irAE), some of which can be life-threatening and debilitating, including cardiomyositis, encephalitis, and adrenal insufficiency, among others. Hence, there is an unmet need to identify biomarkers in the tumor microenvironment which could predict patients who may attain pCR with chemotherapy alone and be spared the side effects from the added PD-1 inhibition. Methods: Comprehensive immune profiling, including PD-L1 IHC and the expression of 395 immune genes by RNA-seq, was performed on 1:2 matched FFPE tumor samples from 23 stage 1-3 TNBC patients (2 stage 1, 6 stage 2, 15 stage 3). All patients were female with an average age of 48 years (range: 25-79 years). 14 patients were treated with neoadjuvant chemotherapy alone (NAC) and 9 were treated with neoadjuvant chemotherapy combined with the checkpoint inhibitor pembrolizumab (NAC+I). mRNA expression signatures of tumor inflammation (TIGS, weak/moderate/strong), cell proliferation (CP, poor/moderate/high), and cancer testis antigen expression burden (CTAB) were determined by RNA-sequencing. Statistical comparisons of quantitative biomarkers between groups were calculated using the Wilcoxon Rank-Sum test, overrepresentation analysis of categorical variables between groups was calculated by proportions test, and survival differences were quantified by Cox proportional hazards analysis. Pathological responses were documented as pathological complete response (pCR) vs. non-pCR. Results: Across the entire cohort, patients with a BMI < 30 had significantly higher PD-L1 expression (assessed by RNA) than those with a BMI ³ 30 [p=0.047]. While not a statistically significant association, the NAC+I group tended to have a higher pCR rate compared to the NAC group [44.4% vs. 28.6%, p=0.66]. Across the entire cohort, tumors with high CTA expression, designated as CTAB high, had a higher pCR rate than CTAB low tumors [54.5% vs 16.7%, p=0.089]. No significant difference in pCR rate between TIGS or CP groups was detected for the NAC group, but in the NAC+I group, highly proliferative tumors had a lower pCR rate than moderately proliferative tumors [0% vs. 80%, p=0.048]. The pCR and non-pCR groups for each treatment type also exhibited distinct gene expression profiles. Among the NAC group, underexpression of FOXP3 and overexpression of MAPK14 and CD44 were associated with pCR [p≤0.031], while underexpression of IFNB1, MAPK14, and CD44 was associated with non-pCR [p≤0.029]. Among the NAC+I group, overexpression of CXCR4, TNFR and CCL20 was associated with non-pCR [p≤0.046]. Interestingly, SDHA was significantly overexpressed in the non-pCR subset of patients in the NAC group and significantly underexpressed in the non-pCR subset of patients in the NAC+I group [p≤0.031]. Conclusions: The development of biomarkers of treatment response is essential to the integration of immunotherapy with chemotherapy as a combined cancer treatment. Our study profiled the immune context of both NAC and NAC+I and identified several key microenvironmental differences underlying divergent treatment response in both groups. A comprehensive understanding of these factors could potentially predict pCR to chemotherapy alone, enabling the avoidance of the unnecessary treatment of these tumors with immunotherapy. Citation Format: Robert Seager, Heidi Ko, Sarabjot Pabla, Maria-Fernanda Senosain, Pawel Kalinski, Erik Van Roey, Shuang Gao, Kyle Strickland, Rebecca Previs, Mary Nesline, Stephanie Hastings, Shengle Zhang, Jeffrey Conroy, Taylor Jensen, Marcia Eisenberg, Brian Caveney, Eric Severson, Shakti Ramkissoon, Shipra Gandhi. Comprehensive immune profiling reveals factors associated with neoadjuvant chemotherapy response in triple negative breast cancer [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 PO4-25-03.

Abstract PO1-01-04: The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis

Abstract Background In patients with the HR+/HER2+ breast cancer (BC) subtype, it can be more challenging to achieve pathological complete response (pCR) after neoadjuvant therapy compared with the HR-/HER2+ subtype. The importance of neoadjuvant therapy and the association of pCR with long-term clinical benefits have been widely demonstrated in HER2+ BC. This network meta-analysis aimed to identify the optimal anti-HER2 regimen, the role of endocrine therapy, and the better chemotherapy choice for the neoadjuvant treatment of HR+/HER2+ BC patients. Methods Literature for neoadjuvant clinical trials in HR+/HER2+ breast cancer was searched in Medline, EMBASE, Cochrane Library, and Web of Science for publications released before June 2023. Single-arm trials, retrospective studies, and observational studies were excluded, as well as studies containing no neoadjuvant phase and/or no anti-HER2 drugs. A network meta-analysis with the fixed-effect model in a Bayesian framework was performed. Odds ratios (ORs) with 95% confidence intervals (CI) for pathological complete response (pCR) analysis and hazard ratios (HRs) with 95% CI for event-free survival (EFS) were calculated. A ranking of treatment patterns was performed using SUCRA. (Registered in PROSPERO: CRD42023385644 Results 2,844 records were identified by the literature search, 60 trials were included after the screening, and valid data were extracted. 19 trials and 2,883 patients were included in the primary analysis of pCR. Compared with trastuzumab + chemotherapy (CT), three treatment regimens showed significantly higher pCR rates, T-DM1 based treatment (T-DM1, OR: 2.83, 95% CI: 1.90, 4.27; which includes T-DM1 alone, T-DM1 + pertuzumab or T-DM1 + endocrine therapy), trastuzumab + pertuzumab + CT (PH, OR: 2.57, 95% CI: 1.70, 3.94), and trastuzumab + tyrosine kinase inhibitor (TKI)+ CT (H+TKI, OR: 1.60, 95% CI: 1.22, 2.09; TKI includes lapatinib, neratinib and pyrotinib). The SUCRA ranking of pCR showed that T-DM1 was ranked first (SUCRA: 0.94), followed by PH (SUCRA: 0.85) and H+TKI (SUCRA: 0.60). PH came first in the SUCRA ranking of EFS (SUCRA: 0.74) as well as cumulative SUCRA combining pCR and EFS (SUCRA: 0.79). For chemotherapy strategies, platinum-containing regimens showed no significant increase in pCR rate compared to no platinum regimens (OR: 1.27, 95% CI: 0.95, 1.69), regimens with anthracycline also had no statistical difference from those without anthracycline (OR: 0.74, 95% CI: 0.51, 1.07). When assessing the impact of endocrine therapy, no significant difference in pCR rate was observed with or without endocrine therapy (OR: 1.18, 95% CI: 0.80, 1.73). Conclusions The PH regimen remains the best neoadjuvant treatment choice for HR+/HER2+ early BC patients considering pCR and EFS outcomes simultaneously. H+TKI did not show significant benefits, so it is not recommended to be given priority in clinical practice. The platinum-containing regimen’s potential benefit compared to the non-platinum regimen is uncertain and needs more clinical investigation. The necessity of adding endocrine therapy is not proven due to limited data availability. Funding: This study was sponsored by Shanghai Roche Pharmaceuticals Ltd. Disclosure: Hao Tang, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Yajing Feng, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Xin Yu, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Citation Format: Hao Wang, Shiwei Liu, Miao Yu, Kun Mi, Exian Mou, Li Xia, Weimin Xie, Hao Tang, Yajing Feng, Xin Yu. The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis [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 PO1-01-04.

Real-world data on neoadjuvant chemotherapy with dual-anti HER2 therapy in HER2 positive breast cancer

BackgroundNeoadjuvant chemotherapy with dual-targeted therapy is the standard treatment for human epidermal growth factor 2 (HER2)-positive breast cancer. Although the dual-targeted therapy has significantly improved the pathological complete response (pCR) rate, further investigation is needed to identify biomarkers that predict the response to neoadjuvant therapy.MethodsThis retrospective study analyzed 353 patients with HER2-positive breast invasive ductal carcinoma. The correlation between clinicopathological factors and pCR rate was evaluated. A nomogram was constructed based on the results of the multivariate logistic regression analysis to predict the probability of pCR.ResultsThe breast pCR (b-pCR) rate was 56.1% (198/353) and the total pCR (t-pCR) rate was 52.7% (186/353). Multivariate analysis identified ER status, PR status, HER2 status, Ki-67 index, and neoadjuvant chemotherapy regimens as independent indicators for both b-pCR and t-pCR. The nomogram had an area under the receiver operating characteristic curve (AUC) of 0.73 (95% CI: 0.68–0.78). According to the nomogram, the t- pCR rate was highest in the ER-PR- HER2-positive patients (131/208) and lowest in the ER + PR + HER2-positive patients (19/73). The subgroup analyses showed that there was no significant difference in pCR rate among the neoadjuvant chemotherapy regimens in ER positive, PR positive, HER2 IHC 2 + , Ki67 index < 30% population. However, for ER-PR-HER2-positive patients, the neoadjuvant chemotherapy regimen has a great influence on the pCR rates.ConclusionsPatients with ER-negative, PR-negative, HER2 3 + and high KI-67 index were more likely to achieve pCR. THP may be used as an alternative to AC-THP or TCbHP in selected HER2-positive patients.

Clinicopathological characteristics and value of HER2-low expression evolution in breast cancer receiving neoadjuvant chemotherapy

ObjectiveThe present study aimed to evaluate the clinicopathological characteristics and value of HER2-low expression evolution in breast cancer receiving neoadjuvant chemotherapy (NAC). MethodsPatients with HER2 negative breast cancer receiving NAC from January 2017 to December 2020 were enrolled in this study. The clinicopathological characteristics, response to NAC, evolution of HER2 and prognostic value were retrospectively analyzed. Results410 patients were included. The proportion of HR positive disease in HER2-low cases was higher than in HER2-zero population (75.8 % vs. 65.8 %, P = 0.040). No statistical significant difference in pCR rate was observed between HER2-low and HER2-zero patients (33.8 % vs. 39.3 %, P = 0.290) when pCR was defined as ypTis/0ypN0. Exploratory analysis revealed that the pCR rate of HER2-low cases was significantly lower than HER2-zero patients in the entire population (19.8 % vs. 33.3 %, P = 0.004) and HR positive population (12.6 % vs. 29.9 %, P = 0.001) when pCR was defined as ypT0ypN0. The evolution rate of HER2 expression after NAC was 31.0 % in HER2-zero patients and 24.7 % in HER2-low patients. Compared with patients with HR positive disease, patients with TNBC had higher evolution rate of HER2 expression after NAC (37.7 % vs. 23.6 %). Significant association was observed between HER2 evolution with histology type and Ki-67 index in HER2-zero patients and with lymph node involvement, HR status and Ki-67 index in HER2-low patients. Prognostic impact of HER2 evolution was not observed. ConclusionsHR positive and HR negative HER2-low breast cancer exhibit different clinicopathological features, response to NAC and HER2 evolution after treatment.

Anaemia and pathologic complete response rate according to carboplatin dose in HER2+ breast cancer treated with neoadjuvant TCHP.

Grade 3/4 anaemia, which is mainly induced by carboplatin, frequently occurs in patients treated with neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP). However, dose reduction of carboplatin may raise concerns about the oncological outcome. This study investigated the pathologic complete response (pCR) rate, occurrence of grade 3/4 anaemia, and transfusion rate according to carboplatin dose in patients treated with neoadjuvant TCHP. We retrospectively analysed 294 patients treated with neoadjuvant TCHP between April 2015 and December 2020. Case matching was performed using propensity score matching. Among patients treated with neoadjuvant TCHP, carboplatin area under the plasma concentration-time curve 6 (AUC6) was used in 234 patients (79.6%) and upfront carboplatin AUC5 was used in 60 patients (20.4%). No significant difference in pCR rate was found between the two groups (AUC6: 70.9%, AUC5: 80.0%). In both oestrogen receptor-positive (ER+) and ER- patients, no significant differences were observed between the AUC6 and AUC5 groups (ER+: 54.3% vs. 50.0%, ER-: 81.7% vs. 86.0%). The case-matched cohort showed consistent findings. The AUC5 group had lower frequencies of grade 3/4 anaemia (18.3% vs. 34.2%) and transfusion events (10.0% vs. 21.8%) than the AUC6 group. Compared with AUC5, carboplatin at AUC6 would associate with a 2.7-fold increased risk of grade 3 or 4 chemotherapy-induced anaemia. Carboplatin AUC5 has comparable cytotoxic effects to carboplatin AUC6 in patients with HER2+ breast cancer treated with six cycles of neoadjuvant TCHP, with fewer complications associated with clinically meaningful anaemia. AUC5 may be the optimal carboplatin dose to reduce TCHP-induced anaemia in patients with HER2+ breast cancer treated with TCHP.

Dose-dense neoadjuvant chemotherapy in triple-negative breast cancer: Real-world data from a developing country.

e12594 Background: Dose-dense adjuvant chemotherapy has been shown to be associated with improved long-term survival outcomes in triple-negative breast cancer (TNBC). However, there is a lacuna of data on the benefits of dose-dense neo-adjuvant chemotherapy (NACT) in TNBC particularly with respect to pathological complete response (pCR) rates and with the relapse or overall survival. To our knowledge no studies have been reported regarding the use or benefit of dose-dense NACT (ddNACT) over conventional NACT (cNACT) among Indian women with TNBC. Methods: This retrospective study included, 217 newly diagnosed cases of TNBC, treated with sequential anthracycline and taxane based NACT followed by definitive surgery. Study groups consisted of 137 patients who received 3-weekly conventional chemotherapy (cNACT group) and 80 patients with 2-weekly dose-dense NACT (ddNACT group) with granulocyte-colony-stimulating factor (GCSF) prophylaxis. Primary endpoint of the study was pathological complete response (pCR) rate and secondary endpoints were relapse-free survival (RFS), overall survival (OS) and grade-3/4 chemotoxicities. Fisher’s exact test was used to compare pCR rates. Kaplan-Meier and cox regression survival analysis were used to compare survival outcomes. Results: Median age (Interquartile range) in overall population, cNACT and ddNACT group were 43 (37-50), 44 (37-50) and 42 (36.5-48) years respectively. Baseline parameters were comparable between study groups, except that ddNACT group had higher proportion of premenopausal patients as compared to cNACT group (72.5% vs 55.5%). Majority of the patients presented at advanced stage, with stage-III being predominant, constituted by 97 (70.1%) and 55 (67.5%) patients in cNACT and ddNACT group respectively. No significant difference in pCR rate (32.8% vs 31.3%; p=0.808) was observed across the study groups. In multivariate analysis, dose-dense chemotherapy was no better than conventional chemotherapy for achieving pCR (Odds ratio [OR]: 0.86, 95% confidence interval [CI]: 0.45-1.63; p=0.639 and had no RFS advantage over conventional chemotherapy [Median RFS: Not reached in ddNACT vs 56.1 months in cNACT; Hazard Ratio: 0.83, 95% CI (0.48-1.44)]. OS was also comparable in both the groups with 3-year survival rate of 78.8% (95%CI: 60.9-89.2) in ddNACT group vs 84.3% (95% CI: 74.8-90.4) in cNACT group. Grade-3/4 toxicities were comparable in both groups. Conclusions: This observational study focusing on ddNACT among TNBC patients demonstrated similar pCR and toxicity rates with no significant survival benefits compared to cNACT regimen. Cost-benefits of frequent hospital visits for GCSF administration associated with dose dense therapy need further consideration before implementing such these regimens in lower-middle income countries.

Concurrent use of statins and neoadjuvant chemoradiotherapy for rectal cancer: a systematic review and meta-analysis.

Statins are used primarily in patients with cardiovascular disease. More recently, they have demonstrated benefit in oncology patients. In vitro models have shown decreased rectal tumor cell viability in cells receiving chemoradiation and statin therapy. In vivo models have been less clear. This study aims to elucidate the impact of concurrent use of statins on the efficacy of neoadjuvant therapy for rectal cancer. Search of Medline, EMBASE, and CENTRAL was performed. Articles were included if they reported complete pathological response (pCR), long-term oncologic outcomes, or chemoradiotherapy-induced toxicity in patients with rectal cancer receiving concurrent statin and neoadjuvant therapy. A pairwise meta-analyses was performed using inverse variance random effects. From 1564 citations, six studies with 726 patients on statin therapy (24.5% female, age: 63.6years) and 1863 patients not on statin therapy (35.6% female, age: 60.9years) were included. There was no significant difference in pCR rate between patients on statin therapy and patients not on statin therapy (RR 1.23, 95%CI 0.98-1.54, p = 0.08). Similarly, no difference existed between groups in long-term oncologic outcomes (5-year overall survival: RR 1.03, 95%CI 0.86-1.24, p = 0.75; 5-year disease-free survival: RR 1.04, 95%CI 0.85-1.26, p = 0.73). Chemoradiotherapy-induced toxicities were similar between groups. The concurrent use of statin and neoadjuvant therapy did not significantly impact short- or long-term oncologic outcomes in patients with rectal cancer. Yet, despite pooling of data, this study remained inadequately powered. Larger, prospective studies are required to further elucidate the impact of statins on patients undergoing neoadjuvant therapy for rectal cancer.

Germline alterations other than BRCA in triple negative breast cancer (TNBC) patients who underwent neoadjuvant therapy (NAT) on a prospective clinical trial.

1546 Background: Previous studies have related germline BRCA mutations to pathologic complete response (pCR) in TNBC cohorts. However, prospective data is lacking on the frequency of non- BRCA germline mutations and pCR in TNBC patients who received neoadjuvant therapy (NAT). The aim of this study was to describe germline alterations in comparison with pCR in a prospective cohort of TNBC receiving NAT. Methods: Pre-NAT blood was drawn from patients enrolled in a clinical trial of genomically tailored NAT (ARTEMIS: NCT: 02276443, per eligibility patients had to have negative clinical BRCA tetsing). Germline DNA was extracted and sequenced on a HiSeq4000 sequencer (Illumina, coverage 60X). Reads were aligned to human reference hg19. Variants were filtered against public databases of normal cohorts: esp6500, 1000 genome, ExAC with a frequency cutoff at 1% in any ethnicity. Two integrative scores were used to evaluate the deleteriousness of the missense variants and the variants predicted to be damaging by both scores were included in the analyses. A 105 pan-cancer susceptibility gene panel was selected based on literature data and commercially available gene panels. NAT included anthracycline and taxane based chemotherapy +/- targeted therapy based on tumor genomic expression. Univariate logistic regression models were used to fit pCR for individual mutations, excluding genes mutated in fewer than three patients. All statistical analyses were performed using R version 3.6.1. with a significance of p=0.05. Results: Germline results and pCR were available for 152 patients. Median age was 55 yrs (range: 24-77). 7.9% were stage (st) I, 65.8% st II, 26.3% st III. 55 pts (36%) had pan-cancer associated germline mutations, whereas 33 (21%) had a breast-cancer associated mutation. Greater than 1% mutations were seen in seventeen genes (Table). There was no significant difference in pCR rate after NAT among pts with different germline mutations versus without mutation. Conclusions: Breast cancer related germline mutations other than BRCA in TNBC are relatively common supporting at least a breast panel (not only BRCA1/2) testing. Treatment implications of different germline mutations and their impact on pCR is ongoing on an extended series. [Table: see text]

Microsatellite instability and response to neoadjuvant chemoradiotherapy in rectal cancer: A systematic review and meta-analysis

BackgroundResponse to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer is variable. Identification of biomarkers to predict response is desirable in order to provide prognostic information and targeted therapy. Several studies have investigated microsatellite instability (MSI) as a predictor of response to CRT with contradictory results. This study aims to clarify the effect of MSI status on response to CRT in locally advanced rectal cancer through systematic review and meta-analysis. MethodsA systematic search of PubMed, Embase and Cochrane databases was performed for all studies relating to MSI and response to CRT in rectal cancer using the search algorithm (Microsatellite Instability) AND (Chemoradiotherapy) AND (Rectal Cancer). From each included study the number of patients with MSI tumors and Microsatellite Stable (MSS) tumors and the numbers achieving pathological complete response (pCR) were recorded. Pooled outcome measures were determined using a random effects model and the odds ratio estimated with variance and 95% confidence interval. ResultsNine published studies were identified reporting data on MSI and its effect on outcome after CRT for locally advanced rectal cancer. Five studies describing 5,877 patients included data on MSI and the number of patients achieving pCR. There was no significant association between MSI and pCR (MSI Vs MSS: 10.1% Vs 6.6%, OR 1.38, 95% CI: 0.7–2.72, p = 0.35). ConclusionThis meta-analysis concludes that there appears to be no significant difference in pCR rate following CRT in patients with MSI versus MSS rectal tumors.

280P - Defining a SUV decrease cut-off in PET/CT response monitoring after one cycle of preoperative breast cancer chemotherapy

BackgroundA decrease in tumor metabolic activity have been shown to be an early indicator of treatment effectiveness for breast cancer. MethodsWe reviewed the records of patients enrolled to the prospective study of prediction of preoperative chemotherapy response (MILESTONE-BreastPred). In the whole group PET/CT was used as an initial method of staging and as response assessment after 1st cycle of chemotherapy. We analysed data of 425 patients, 19.8% TNBC, 12.2% nonluminal HER2-positive and 68% luminal cancers. 88% of patients were stage II or III. pCR rate was 24.8% (ypT0/is ypN0). 31.1% of patients showed progressive disease during follow-up. The aim of the study was to assess the clinical utility of various cut-offs of SUVmax decrease to predict both pCR and disease relapse. ResultsWe analysed SUVmax decrease cut-off of 20%, 30%, 40%, 50 and 60%. For pCR prediction, the sensititivity was above 50% for cut-offs 20%-40%, while specificity exceeded 50% for cut-off values 40-60%. In the whole range of cut-offs, there was highly statistically significant difference in pCR rate between low and high SUVmax decrease (p<0.001). Cut-off of 40% was chosen, providing optimal trade-off between sensitivity and specificity with positive likelihood ratio 1.89, negative likelihood ratio 0.49, PPV 38.4% and PPV 86.0%. Prediction of disease relapse based on 1st cycle SUVmax decrease was more challenging, with sensitivity above 50% for cut-offs 20-30% and specificity above 50% for cut-offs 40-60%. For cut-off 40% the difference in disease relapse between groups was closest to the limit of statistical significance (p=0.085) and provided PLR 0.81, NLR 1.17, PPV 26.6% and NPV 65.6%. ConclusionsPrediction of pCR by 1st cycle SUVmax decrease was feasible, with good balance of specificity and sensitivity for cut-off 40%. This cut-off provides the most prominent, although not significant in this analysis, association with the risk of disease relapse. The study was supported by the Polish National Center of Research and Development MILESTONE project–Molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant no.STRATEGMED2/267398/4/NCBR/2015. Legal entity responsible for the studyThe authors. FundingThe study was supported by the Polish National Center of Research and Development MILESTONE project – Molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant no. STRATEGMED 2/267398/4/NCBR/2015. DisclosureAll authors have declared no conflicts of interest.

Treatment Interval between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer Patients: A Population-Based Study.

Background Neoadjuvant chemoradiation therapy (CRT) has been widely implemented in the treatment of rectal cancer patients, but optimal timing of surgery after neoadjuvant therapy is unclear. The purpose of this study was to evaluate the effects of prolonged intervals between long-course CRT and surgery in rectal cancer patients.MethodsData on all rectal cancer patients diagnosed between 2006 and 2011 were retrieved from the population-based Netherlands Cancer Registry; the main outcome parameters were pathologic complete response (pCR) and overall survival (OS). Outcomes were reported separately for patients with early tumors (ETs; N = 217) and locally advanced rectal cancer (LARC; N = 1073). Patients were divided into 2-week interval groups according to treatment interval, ranging from 5–6 to 13–14 weeks. Kaplan–Meier curves, and logistic regression and Cox regression models were used for data analysis.ResultsNo significant difference in pCR rate was observed for ET patients according to treatment interval. Compared with a treatment interval of 7–8 weeks, pCR rates in LARC patients were higher after 9–10 weeks (18.4 %; odds ratio [OR] 1.56, 95 % CI 1.03–2.37) and 11–12 weeks of treatment interval (20.8 %; OR 1.94, 95 % CI 1.15–3.26). Treatment interval did not influence OS in ET or LARC patients.ConclusionsTreatment intervals of 9–12 weeks between surgery and CRT seem to improve the chances of pCR in LARC patients, without an effect on OS. The length of treatment interval did not affect outcomes in patients with ET. The ongoing search for minimally invasive surgery drives the need for exploration of factors that improve pathologic response.Electronic supplementary materialThe online version of this article (doi:10.1245/s10434-016-5294-0) contains supplementary material, which is available to authorized users.

Abstract S2-04: Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto)

Abstract Introduction Addition of carboplatin to anthracycline/taxane-based neoadjuvant chemotherapy has shown to improve pathological complete response (pCR; ypT0 ypN0) rates in patients with triple-negative breast cancer in two large phase II studies (GeparSixto: von Minckwitz et al. Lancet Oncol 2014; CALGB 40603: Sikov et al. J Clin Oncol 2015). Participants of the GeparSixto study with triple-negative tumors showed an improvement of pCR rate from 36.9 to 53.2% by the addition of carboplatin (p=0.005); however, no statistically significant difference in pCR rate was observed in the HER2-positive subgroup (36.8 vs 32.8%, respectively). A greater benefit with carboplatin was observed in patients with BRCA mutations or a high homologous recombination deficiency (HRD score) in the tumor (pCR rate of 30% compared to 10% for patients without HRD). So far, it is unknown whether these effects on pCR translate into a survival benefit for the patients. We here report an early survival analysis of the GeparSixto study. Patients and Methods In the GeparSixto trial (NCT01426880), patients were treated for 18 weeks with paclitaxel 80mg/m2 q1w and non-pegylated-liposomal doxorubicin (NPLD) 20mg/m2 q1w. Patients with TNBC (N=315) received concurrently bevacizumab 15mg/kg i.v. q2w until surgery. Patients with HER2+ disease (N=273) received concurrently trastuzumab 6(8)mg/kg q3w and lapatinib 750mg daily. All patients were randomized 1:1 to receive concurrently carboplatin AUC 1.5-2.0 q1w vs no carboplatin, stratified by subtype (HER2+ vs TNBC). Carboplatin dose was reduced from AUC 2.0 to 1.5 by an amendment after 330 patients. Primary objective was pCR rate (ypT0 ypN0). Loco-regional invasive recurrence free survival (LRRFS), distant-disease- free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS) were secondary objectives. Results 595 patients were recruited (8/2011 - 12/2012) in 51 German centers. 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. So far, 82 events have been reported after a median of 28 months follow-up. Analysis of updated events by treatment arm in the full study population as well as in the TNBC and HRD subgroups will be presented. Conclusion Even if the GeparSixto study was not powered to show carboplatin effects on survival, the expected results will help to assess the overall benefit of carboplatin in TNBC and the power of pCR to predict for DFS and OS. Citation Format: von Minckwitz G, Loibl S, Schneeweiss A, Salat CT, Rezai M, Zahm D-M, Klare P, Blohmer J-U, Tesch H, Khandan F, Fasching PA, Jakisch C, Nekljudova V, Untch M. Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). [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 S2-04.

Abstract P1-14-02: Preoperative docetaxel (T) with or without capecitabine (X) following epirubicin, 5-fluorouracil and cyclophosphamide (FEC) in patients with operable breast cancer (OOTR N003): Results of comparative study and predictive marker analysis

Abstract Objective: This preoperative study aimed to evaluate the efficacy of 4 cycles of TX compared with 4 cycles of T, following 4 cycles of FEC in operable breast cancer patients. Methods: Women with operable breast cancer (T1C-3N0M0/T1-3N1M0) were randomly assigned to receive either T (75 mg/m2, q3) plus X (825 mg/m2 bid, days 1 to 14) or T alone (75 mg/m2, q3) after completion of FEC (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2, q3). Patients who had disease progression on FEC were excluded from randomization. The primary endpoint was pathological complete response (pCR). Predictive factor analysis was conducted using clinicopathological markers such as hormone receptors, Ki67 labeling index (Ki67LI) and thymidine phosphorylase (TP). Results: From November 2005 to October 2009, 504 patients were enrolled and 239 and 238 patients were assigned to TX and T group, respectively (median age 49 years, median tumor size 3.5 cm and node positive rate 56%). Treatment discontinuation was observed in 22% of TX group and 5% in T group (p &amp;lt; 0.0001). The major reasons for discontinuation were toxicity, refusal/ consent withdrawal and several others. No significant difference in pCR rate was shown between the two groups (TX 23% and T 24%, p = 0.748). Neither clinical response nor surgical outcome differed between TX and T. The pCR rate in patients who had therapy discontinuation or dose-reduction on TX was 23%, whereas pCR rate in those on T was 11%. A subpopulation treatment effect pattern plots method indicated a trend that TX may improve the pCR rate in patients having a middle range of pretreatment Ki67LI, such as 10%–20%. In the median follow-up time of 3.7 years, disease-free survival (DFS) was not different between TX and T (3-year DFS: 92% in TX and 91% in T; hazard ratio 0.907, 95%CI 0.528–1.557, p = 0.723). The frequency of major grade 3 or greater adverse events of TX and T were leukopenia, 36% and 34%, febrile neutropenia 8% and 5%, and hand-foot syndrome 15% and 2%, respectively. According to the analysis for evaluating predictive values of biomarkers, a multivariate logistic regression analysis showed that HER2 (+/−: odds ratio 4.107, p &amp;lt; 0.0001), Ki67LI (continuous variables: 1.029, p = 0.003), hormone receptor status (+/−: 0.457, p = 0.009), stroma TP status (0.523, p = 0.02) and grade (1/3: 0.387, 2/3: 0.532, p = 0.047) had statistical significant values for predicting pCR. A multiple Cox model in landmark analysis showed that tumor size (p &amp;lt; 0.0001), cancer cell TP status (p = 0.005), pCR and posttreatment Ki67LI (p = 0.016), and age (p = 0.049) were associated with DFS significantly. Conclusions: Addition of X to T showed no superiority to T alone following FEC in neoadjuvant treatment of these patients with operable breast cancer. Treatment discontinuation rate was significantly higher in TX than T group, however the pCR rate in patients in TX group who required treatment discontinuation or dose-reduction was similar to that in patients who completed as scheduled, which was different from T group. Determination of pre-/ post-treatment Ki67LI looks useful for predicting pCR and DFS. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-02.

Abstract P1-14-16: Young age: predicts poor response rate after neoadjuvant chemotherapy in endocrine-responsive breast cancer

Abstract Background: Breast cancer rarely occurs in very young women(age&amp;lt;35years), its diagnosis and management could sometimes be difficult. Especially, the patients with positive hormone receptors have significantly lower overall and disease-free survival rates in very young age group than in the older age group. In the previous study, adjuvant tamoxifen therapy might provide less survival benefit when added to chemotherapy in very young breast cancer patients. This study was to compare the response to neoadjuvant chemotherapy for HR-positive breast cancer patients according to the age. Patients and Methods: A total of 551 consecutive patients were evaluated, received preoperative chemotherapy and referred to surgery at the Seoul National University Hospital from January 2001 to December 2010. The clinicopathologic factors and the response to neoadjuvant chemotherapy between the very young age group and the older age group were retrospectively compared. A pCR was defined as the absence of residual invasive carcinoma in the breast. Results: Among the 551 patients who received neoadjuvant chemotherapy, 297 patients revealed HR-positive. The median age of all patients was 42 (range, 24∼67)years and very young age group accounted for 17.2%(51/297). Of 297 patients, 262 (88.2%) received taxane-containing regimen pre-operatively, and there's no difference of chemotherapeutic regimen between two age groups. There were no differences noted between two age groups about clinicopathologic characteristics. The univariate and multivariate analysis of variables related to ORR(CR+PR vs SD+PD) to neoadjuvant chemotherapy showed that very young age at diagnosis was independent predictive factor for poor neoadjuvant chemotherapeutic response.(p = 0.043, OR = 0.528) And this tendency was observed more significantly in age under 30.(p = 0.001, OR = 0.147) Only thirteen patients(4.4%) achieved pCR, which is relatively lower rate, reflective poor chemotherapeutic response in HR-positive group, and there was no relations between pCR rate and the two age groups(p = 0.861) in this study. Taxane-containing regimen(p = 0.004) and Ki67 level(p = 0.005) were related to pCR statistically significantly. Breast conservation rate is not significantly different between two age groups.(age&amp;lt;35: age&amp;gt;35= 51.2% vs 41.3%, p = 0.150) Conclusions: The very young age group showed lower ORR(CR+PR) to neoadjuvant chemotherapy, although there was no significant difference in pCR rate between the two age groups in HR-positive breast cancer patients. We might have to consider and revalue the chemotherapeutic role as neoadjuvant therapy in very young age, HR-positive group, since they had lower survival rate than others. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-16.

Randomized Phase II Study of Primary Systemic Chemotherapy and Trastuzumab for Operable HER2 Positive Breast Cancer

Background In primary systemic therapy in patients with human epidermal growth factor receptor 2 positive (HER2 +) breast cancer, improvements in pathologic complete response (pCR) rate have been achieved by administering trastuzumab. Patients and Methods Patients with stage II or IIIA HER2 + operable breast cancer were randomly assigned to receive four 3-weekly cycles of FEC (5-fluorouracil 500 mg/m 2, epirubicin 100 mg/m 2, cyclophosphamide 500 mg/m 2) followed by 4 cycles of 3-weekly trastuzumab (8 mg/kg week 1 and then 6 mg/kg) with either 12 weekly doses of paclitaxel 80 mg/m 2 (FEC-PH) or 4 cycles of 3-weekly docetaxel 75 mg/m 2 (FEC-DH). Results Between March 2007 and June 2008, 102 patients were enrolled. Forty-nine patients receiving FEC-PH and 47 receiving FEC-DH were assessable for efficacy and safety. Eighty-four patients completed treatment and underwent surgery. There was no significant difference in the pCR rate between the 2 groups (46.9% [95% CI, 33.7%-60.6%] with FEC-PH vs. 42.6% [95% CI, 29.5%-56.8%] with FEC-DH; P = .67). Analysis by hormone receptor (HR) status showed pCR rates of 54.2% (32/59) in HR − tumors and 29.7% (11/37) in HR + tumors ( P = .02). Among HR − tumors, the pCR rates were 65.4% and 45.5% in patients treated with FEC-PH and FEC-DH, respectively ( P = .13). Conclusions There was no significant difference in pCR rate between FEC-PH and FEC-DH. Both regimens achieved higher pCR rates in HR − than HR + breast cancer, and there was a trend toward higher pCR in HR − tumors with FEC-PH compared with FEC-DH. Further investigation is warranted to explore the relationship between efficacy and HR status.

Abstract P1-11-04: A Phase II Preoperative Trial of Concurrent Trastuzumab and Paclitaxel without Anthracycline in HER2-Positive Operable Breast Cancer

Abstract Background Concurrent trastuzumab with paclitaxel/fluorouracil, epirubicin, and cyclophosphamide (P/FEC) chemotherapy as neoadjuvant treatment revealed the high pathologic complete response (pCR) rate of 54.5% (Buzdar, 2007). Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway either through loss of PTEN or mutation of the catalytic subunit alpha of PI3K (PIK3CA) might confer resistance to trastuzumab. The objective of this study was to determine the efficacy of concurrent administration of trastuzumab and paclitaxel wtihout anthracycline as preoperative chemotherapy. The correlation between deregulation of PI3K and resistance to trastuzumab was also investigated. Patients &amp; methods Patients with HER2-positive, operable breast cancer received 12 cycles of weekly paclitaxel (80 mg/m2) and trastuzumab (4mg/kg loading dose then 2 mg/kg) for 12 weeks before surgery. PTEN status was evaluated by immunohistochemistry. PTEN staining intensity scores was recorded on an integer scale from 0 to 2+ (0; no staining, 1+; reduced staining, and 2+; equal staining as compared to the internal control). Sequencing of PIK3CA exons 9 and 20 was done by PCR amplification and direct sequencing. pCR was defined as no residual invasive carcinoma in the breast. Results Twenty-eight patients were enrolled and assessable for clinical and pathologic responses. The overall response rate was 92.9%, including a complete response in 13 patients and a partial response in 13 patients. The pCR rate was 53.6% (15/28). Twenty-three patients (82.1%) underwent breast concerving surgery. Progesteron receptor (PgR) status was significantly correlated with pCR (p=0.025). Eight of 24 patients (33.3%) were scored PTEN negative. PIK3CA mutations were identified in 4 of 13 patients (30.8%). There was no significant difference in pCR rate and PTEN loss/PIK3CA mutation. Correlation of PgR status and pCR Conclusions These data indicate that the combination of trastuzumab and paclitaxel without anthracycline is effective preoperative chemotherapy with high pCR rate. PTEN loss and/or PIK3CA mutation were not useful predictors of resistance to trastuzumab. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-04.

Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response

Purpose: Preoperative chemoradiation is being utilized extensively in the treatment of rectal cancer. However, a variety of dose time factors in both delivery of chemotherapy and irradiation remain to be established. This study was undertaken to examine the impact of dose time factors on pathological complete response (pCR) rates following preoperative chemoradiation for fixed rectal cancer. Methods and Materials: Thirty-three patients with fixed rectal cancers were treated with combined 5-fluorouracil (5-FU) chemotherapy and pelvic radiation. Twenty-one patients received bolus 5-FU during the first 3–5 days of radiation and repeated on days 28–33 of their radiation treatment. Twelve patients were treated with continuous infusion (CI) 5-FU, 225 mg/m 2 for the duration of the pelvic radiation. Fifteen patients received a planned total radiation dose of 45 to 50 Gy and 18 patients received a dose of 55 to 60 Gy. Surgical resection was then carried out 6–8 weeks after completion of treatment. Results: Diarrhea was the most frequent acute toxicity. Grade 3 diarrhea was observed in 6 patients requiring treatment interruption and was not related to the chemotherapy regimen. There was no Grade 4 or 5 toxicity. pCR was observed in 2 of 21 (10%) patients treated with bolus 5-FU as compared to 8 of 12 (67%) for patients treated with CI ( p = 0.002). pCR were observed in 8 of 18 (44%) patients receiving radiation dose ≥ 5500 cGy as compared to 2 of 15 (13%) patients treated to a dose ≤ 5000 cGy ( p = 0.05). In the high-dose radiation (≥ 5500 cGy) group, a significant difference in pCR rate was observed in patients treated with CI, 8 of 12 (67%) ( p = 0.017) as compared with bolus 5-FU (0 of 6). There was no significant difference in operative morbidity or in wound healing between patients treated with bolus 5-FU or CI or within the groups treated with low or high doses of radiation. Three patients have developed local recurrence at 14 and 24 months, two in the low-dose group treated with bolus 5-FU and one patient in the CVI group. The overall 5-year survival for the whole group is 71%. Conclusion: Dose intensity of 5-FU and dose of radiation correlate significantly with the likelihood of achieving a pCR. Continuous infusion 5-FU (CI) and a preoperative radiation dose of 5500 cGy or higher can achieve pCR rates of ∼50%, even in fixed cancers of the rectum.