pCR Rate In Patients Research Articles

Effect of neoadjuvant chemotherapy in patients with triple-negative breast cancer: A meta-analysis

The present meta-analysis aimed to evaluate the effect of neoadjuvant chemotherapy on pathological complete response (pCR) and survival rate in patients with triple-negative breast cancer (TNBC). Specific inclusion and exclusion criteria were used to conduct a search of the available databases, in order to find studies performed between January 2006 and January 2014. The bibliographies of the included studies were examined with the same criteria. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group framework was used to evaluate the included studies, and RevMan 5.1 and GRADEprofiler 3.6 were used to analyze the extracted data. A total of 19 studies with 6,180 patients were included. The meta-analysis revealed that the pCR rates in patients with TNBC were significantly higher than those in patients with non-TNBC. The 5-year disease-free survival (DFS) and overall survival (OS) rates were significantly lower in the patients with TNBC compared with those with non-TNBC. Furthermore, these survival rates were significantly higher in the patients with TNBC who achieved a pCR compared with those in the patients who did not achieve a pCR. pCR rates were higher among the patients with TNBC with high Ki-67 expression than among those with low Ki-67 expression. The patients with TNBC exhibited lower survival rates compared with those with non-TNBC, but achieved higher pCR rates. Moreover, those patients achieving a pCR exhibited improved 5-year survival rates, suggesting that the pCR rate could be predictive of survival in patients with TNBC. In addition, high Ki-67 expression may predict the likelihood of a pCR. However, future multicenter randomized controlled trials are required to enhance the quantity and quality of the clinical evidence.

Value of FOXP3 Tregs predicting the effectiveness of neoadjuvant chemotherapy in patients with breast cancer

To explore the predictive significance of FOXP3 Tregs in patients with breast cancer on neoadjuvant chemotherapy (NACT). A total of 78 newly diagnosed and untreated patients with invasive breast cancer were recruited for this retrospective study.FOXP3 Tregs were assessed by immunohistochemistry. The relationship between clinicopathological factors, FOXP3+ Tregs and pathological complete response (pCR) rate was analyzed. Among 78 patients with TAC neoadjuvant chemotherapy, the pCR rate was 19.2%. The pCR rate of patients with high expressions of FOXP3+ Tregs was significantly lower than that of those with low expressions of FOXP3+ Tregs (9.5% vs 30.5%, P = 0.023). FOXP3+ Tregs expression in breast cancer and efficacy of NACT were negatively correlated. FOXP3+ Tregs may serve as a predictor for assessing the efficacy of NACT.

Neoadjuvant dual HER2-targeted therapy with lapatinib and trastuzumab improves pathologic complete response in patients with early stage HER2-positive breast cancer: a meta-analysis of randomized prospective clinical trials.

Randomized clinical trials (RCT) that evaluated the addition of lapatinib to trastuzumab plus neoadjuvant chemotherapy (NAC) in patients with HER2-positive, operable breast cancer revealed a questionable improvement in pathologic complete response (pCR) rate. We performed a meta-analysis of prospective RCTs that examined the effect of adding lapatinib to trastuzumab and NAC on pCR rate. PubMed databases and abstracts from the proceedings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium were searched for RCTs that compared lapatinib plus trastuzumab and NAC with trastuzumab in combination with NAC and that included pCR as the primary outcome. Our main objective was to estimate the effect of adding lapatinib to trastuzumab plus NAC on pCR rate, defined as no residual invasive cancer in breast and axillary lymph nodes. In total, 1,017 patients with early stage breast cancer from 5 trials were included. Four trials examined the addition of lapatinib to trastuzumab plus NAC; this resulted in statistically significant improvement in pCR, defined as no residual carcinoma in breast and lymph nodes. The pCR rate was 55.76% and 38.36% in the lapatinib plus trastuzumab and the trastuzumab plus NAC arms, respectively (odds ratio [OR]: 1.94; 95% confidence interval [CI]: 1.44-2.60). In three trials, the rates of pCR, defined as no residual invasive carcinoma in breast only, for the lapatinib plus trastuzumab and trastuzumab-alone groups were 55.01% and 40.70%, respectively, also resulting in significant improvement (OR: 1.78; 95% CI: 1.27-2.50). The addition of lapatinib to trastuzumab in combination with neoadjuvant chemotherapy significantly improves pCR rates in patients with HER2-positive breast cancer.

Docetaxel and cyclophosphamide as neoadjuvant chemotherapy in HER2- primary breast cancer.

141 Background: Recently, docetaxel plus cyclophosphamide (TC) has been established as a standard regimen for adjuvant chemotherapy in HER2- operable breast cancer. However, the efficacy and tolerability of TC as neoadjuvant chemotherapy (NAC) remains unclear. We performed a prospective study of TC NAC in HER2- primary breast cancer. Methods: Eligible patients had HER2- invasive breast cancer that measured more than 1cm, less than 7cm and N0~N1 clinically between July, 2011 and February, 2014. Four cycles of TC(75 and 600 mg/m2) were administered intravenously every 3 weeks as NAC. We investigated the pathological complete response(pCR) of primary breast tumors. pCR was defined as no histological evidence of invasive carcinoma, or the appearance of only ductal carcinoma in situ. The cut-off value of Ki67 index between luminal A and luminal B was defined 20%. Results: We enrolled 52 patients. The completion rate for 4 cycles of TC was 94.2% ( 49 of 52). Relative dose intensity was 99.1% for TC therapy. Forty nine patients were classified according to breast cancer subtype before the estimation. Overall pCR rate was 16.3 %( 8 of 49 ) . pCR rate for patients with luminal A ( ER+, Ki67 low and HER2- ), luminal B ( ER+, Ki67 high and HER2- ) and triple negative ( ER- and HER2- ) were 0%( 0 of 12 ), 4.3 %( 1 of 23 ) and 50.0 %( 7 of 14 ), respectively pCR was achieved in almost triple negative patients. Conclusions: The pCR rate of TC was not so high, regardless of the high completion rate. In this study, TC was effective against triple negative subtype, showing a high pCR rates, compared with luminal subtype. In conclusion, the efficacy of TC NAC in HER2- primary breast cancer is limited, and triple negative subtype might be the good target. Clinical trial information: UMIN000013261.

Efficacy and safety of neoadjuvant chemotherapy with concurrent liposomal-encapsulated doxorubicin, paclitaxel and trastuzumab for human epidermal growth factor receptor 2-positive breast cancer in clinical practice.

Based on previous results obtained with non-pegylated liposomal-encapsulated doxorubicin (TLC-D99) together with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (BC), a similar regimen was evaluated in the neoadjuvant setting in a prospectively selected series of consecutive patients with clinical stage II-III BC. Primary and secondary objectives included the rate of pathologic complete response (pCR), safety, and predictive factors of pCR. Patients received six cycles of TLC-D99 (50 mg/m(2) every 3 weeks), paclitaxel (80 mg/m(2) weekly) and trastuzumab (4 mg/kg initial dose and 2 mg/kg weekly). All patients underwent surgery after treatment. pCR was defined as the absence of invasive cancer cells in the breast and the axilla. Sixty-two patients with a median age of 46.6 years were analyzed. Stage IIIA was diagnosed in 43.5% of patients and 14.5% had inflammatory BC. Conservative surgery was performed in 46.8% of the patients and pCR was achieved in 63% (95% CI 50.5-75.5). Patients with estrogen receptor (ER)-negative tumors presented a significantly higher pCR rate than patients with ER-positive tumors (74.4 vs 43.5%; P = 0.028). Forty-five patients (72.6%) completed study treatment and 80.6% received at least five treatment cycles. No patients developed congestive heart failure and 14.5% of patients showed a ≥ 10 % decrease in the left ventricular ejection fraction. The triple combination therapy assessed is effective and safe, offering a high pCR rate in patients with HER2-positive BC.

Bevacizumab in neoadjuvant chemotherapy increases the pathological complete response rate in patients with triple‐negative breast cancer

Bevacizumab in neoadjuvant chemotherapy increases the pathological complete response rate in patients with triple‐negative breast cancer

Combination of 5FU-based chemoradiation with EGFR inhibitor cetuximab and effect on PCR rate in patients undergoing neoadjuvant treatment in advanced rectal cancer.

623 Background: Neoadjuvant chemoradiation is a standard treatment for advanced rectal cancer patients. Here, we investigate whether treatment combined with the EGFR inhibitor cetuximab could enhance prognosis. Safety and efficacy (pathohistological regression rate, pCR) of chemoradiation in combination with cetuximab were evaluated. Methods: In a single-center phase I/II study patients with adenocarcinoma of the rectum (up to 16 cm above the anal verge) in stage cT3-4, cN0-1, were treated with cetuximab (weekly 250mg/m2, loading dose 400mg/m2) combined with radiotherapy (50,4Gy in 28 fractions) and 5-FU. Maximal tolerated dose of 5FU in combination with cetuximab and radiotherapy was determined in a phase I part (3+3 design; dose level 1: 750 mg/m2 5FU days 1-5 and 29-33; dose level 2: 1000 mg/m2 5FU days 1-5 and 29-33. Surgery was performed between 4 to 6 weeks after combined treatment. pCR rate of tumor cells was determined after surgery. Results: 20 patients were included into the trial, 19 patients received treatment: In the phase I part 2 out of 6 patients in level 2 experienced dose limiting toxicities (thrombocytopenia and diarrhea grade 3). Therefore, dose level 1 was considered safe for further enrollment. All 19 patients received the complete course of radiotherapy (50,4Gy). 15 patients received the complete cetuximab schedule, one patient discontinued after an allergic reaction at the first infusion, 3 patients missed 1 cycle of cetuximab in week 3 or 6. 18 patients continued to surgery. Sphincter preservation surgery was performed in 12 patients (63.2%), R0-resection rate was 100%. pCR grade IV (pCR) was documented in 1 patient (5,5%), grade III in 4 patients and grade I and II in 13 patients. So far no local recurrences occurred, 4 patients died (3 patients due to metastatic disease progression). Conclusions: The MTD of 5FU in combination with radiotherapy and cetuximab was 750mg/m2. Treatment was well tolerated and did not alter surgical management. However, pCR-rate was not elevated compared to standard 5FU-based preoperative chemoradiation. Whether the addition of cetuximab improves prognosis in this group of patient remains unclear. Clinical trial information: 2005-004139-23.

Abstract P1-08-21: Detection and monitoring of circulating endothelial cells, circulating tumor cells and disseminated tumor cells during neoadjuvant breast cancer treatment including bevacizumab

Abstract Background: Results from studies with bevacizumab in addition to traditional neoadjuvant therapy (NAT) indicate a need for predictive biomarkers. As a sub-study of the NeoAva study (a neoadjuvant study), the aim was to investigate the potential association between the presence of circulating endothelial cells (CECs) in peripheral blood (PB), circulating tumor cells (CTCs) in PB and disseminated tumor cells (DTCs) in bone marrow (BM) at different time points during NAT +/- bevacizumab and at one year follow-up, and therapy response. Patients and methods: A total of 150 HER2-negative patients with cT2-4 (≥ 2.5cm) N0-3 M0 status were randomized to receive NAT with or without bevacizumab. In this sub-study, 90 patients have so far been analyzed. Of these, 82 received chemotherapy (FEC100→taxane) and 8 received endocrine therapy (letrozole) + / - bevacizumab. Therapy response was evaluated according to the RECIST criteria and achievement of pathological complete response (pCR). Number of CECs, CTCs and DTCs were assessed at baseline after 12 weeks, at surgery (after 24 weeks) and at one year follow-up. Blood samples were analyzed by CellSearch® to assess CEC and CTC counts. The detection of DTCs was performed by immunocytochemical analysis of 2 × 106 BM mononuclear cells. Results: The pathological complete response rate was 10 out of 90 (11.1%), eight of these patients received bevacizumab. For bevacizumab-treated patients with a change in CEC counts from baseline to time of surgery below median change (27 CECs), 35% (6/17) achieved pCR compared to 6% (1/18) in the group with a CEC count-increase above median change (p = 0.035). The corresponding pCR rates for patients not receiving bevacizumab (median CEC change 131 CECs) were 0% (0/15) and 13% (2/14), respectively. Stepwise testing of thresholds for CEC changes in the bevacizumab-arm revealed significant associations to pCR for change-values between 20 and 40. CTC- and DTC-status or -changes were not associated with tumor response or CEC changes. Conclusion: The presented results indicate that the level of change in the number of circulating endothelial cells during neoadjuvant therapy including bevacizumab is associated with the pathological complete response rate in breast cancer patients. This supports additional testing of CECs as a surrogate marker for response to this treatment. The analyses will be up-dated with results from the rest of the included patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-21.

Abstract P1-08-42: High HER2 expression correlates with response to trastuzumab and the combination of trastuzumab and lapatinib in the NeoALTTO phase III trial

Abstract Background: Expression of p95HER2, a truncated form of HER2 lacking the extracellular domain, has been associated with resistance to trastuzumab (T)-based therapy in metastatic breast cancer patients. Conversely, high levels of HER2 have been correlated with increased clinical benefit from anti-HER2 therapy in the neoadjuvant setting. In this work we correlated the expression of p95HER2 and HER2 with pathological complete response (pCR) following T, lapatinib (L) or the combination of both agents (T+L) with paclitaxel. Methods: p95HER2 and HER2 were quantified by VeraTag® and HERmark® (Monogram Biosciences), respectively, in primary tumors of 455 patients enrolled in the phase III neoadjuvant study NeoALTTO (Baselga J. et al. Lancet, 2012). The relationship of pCR status to p95HER2 and HER2 was studied using logistic regression models, which accounted for stratification factors and treatment. Unless specified, p95HER2 and HER2 were included as log terms. Results: p95HER2 was measurable in 283 cases (62%) and HER2 in 327 cases (72%). A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) where quantification of both markers was available. Increased HER2 was strongly associated with increased pCR rate in patients treated with the combination of T+L (OR 5.09, 95%CI 2.27-11.44; p<0.01), with a trend observed also in the L-only arm (OR 1.88, 95% CI 0.96-3.70; p = 0.067). Overall, patients with tumors that were HER2-positive (>17.8 RF/mm2) by HERmark had a higher pCR rate than those that were HER2-negative by HERmark (39% vs. 11%, respectively; p<0.001). Increasing p95HER2 levels did not predict for pCR in the L or T+L arms and showed weak evidence (p = 0.073) of an increase in pCR in the T arm. In an unplanned analysis, we examined the odds of achieving response to anti-HER2 therapy in patients with HER2 levels above and below the median (100 RF/mm2, HER2 entered as a binary covariate). HER2 levels above the median predicted a higher response rate to T (OR 3.6, 95% CI 1.2-11; p<0.05) and, more significantly, to T+L (OR 6.01, 95% CI 2.51-14.4; p<0.001). In particular, patients treated with T+L had a higher probability to achieve pCR compared to T alone when HER2 was above the median (T+L = 73% pCR vs. T = 43% pCR, p<0.01; OR 3.74, 95% CI 1.57-8.90), but not when HER2 was below the median (T+L = 29% pCR vs. T = 19% pCR, p>0.2; OR 1.84, 95% CI 0.74-4.55). When tumors were divided in hormone receptor (HR)-positive and HR-negative groups, total levels of HER2 still predicted response to T or T+L. Conclusions: Increasing HER2 protein expression correlated with increased benefit of adding L to T compared to T alone. In tumors above the median of HER2 expression, the levels of HER2 predicted for response to both T and T+L. Our interpretation is that, in the neoadjuvant setting, the association between p95HER2 expression and response to anti-HER2 therapy is likely a consequence of the correlation between p95HER2 and total HER2 levels. HER2 expression seems to be a stronger predictor of pCR than p95HER2 for response to T, L and especially, T+L. Future studies to understand the impact of p95HER2 and HER2 expression on disease-free and overall survival following anti-HER2 therapy are warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-42.

Preoperative Cetuximab, Irinotecan, Cisplatin, and Radiation Therapy for Patients With Locally Advanced Esophageal Cancer

To determine the efficacy and toxicity of weekly neoadjuvant cetuximab combined with irinotecan, cisplatin, and radiation therapy in patients with locally advanced esophageal or gastroesophageal junction cancer. Patients with stage IIA-IVA esophageal or gastroesophageal junction cancer were enrolled in a Simon's two-stage phase II study. Patients received weekly cetuximab on weeks 0-8 and irinotecan and cisplatin on weeks 1, 2, 4, and 5, with concurrent radiotherapy (50.4 Gy on weeks 1-6), followed by surgical resection. In the first stage, 17 patients were enrolled, 16 of whom had adenocarcinoma. Because of a low pathologic complete response (pCR) rate in this cohort, the trial was discontinued for patients with adenocarcinoma but squamous cell carcinoma patients continued to be enrolled; two additional patients were enrolled before the study was closed as a result of poor accrual. Of the 19 patients enrolled, 18 patients proceeded to surgery, and 16 patients underwent an R0 resection. Three patients (16%) had a pCR. The median progression-free survival interval was 10 months, and the median overall survival duration was 31 months. Severe neutropenia occurred in 47% of patients, and severe diarrhea occurred in 47% of patients. One patient died preoperatively from sepsis, and one patient died prior to hospital discharge following surgical resection. This schedule of cetuximab in combination with irinotecan, cisplatin, and radiation therapy was toxic and did not achieve a sufficient pCR rate in patients with localized esophageal adenocarcinoma to undergo further evaluation.

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 < 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 < 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 < 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 P3-06-04: Role of pMAPkinase, pAKT, p27 & IGF-IR as predictive markers of response to trastuzumab in patients with HER2-positive invasive breast cancer treated with neoadjuvant chemotherapy + trastuzumab in the REMAGUS02 trial

Abstract Background: Predicting a benefit from trastuzumab in patients with HER2+ breast cancer remains an important goal. Possible mechanisms of resistance include altered receptor antibody interaction, Akt and MAPK pathways, and loss of p27. The objective of this study was to determine the correlation between pMAPkinase (pMAPK), pAKT, p27, IGF-IR protein expression and the benefit of trastuzumab for patients randomized to chemotherapy (CT) alone and CT with trastuzumab. Patients and methods: From May 2004 to October 2007, 120 patients with stage II and III HER2+ breast carcinomas were enrolled in a phase II trial of neoadjuvant chemotherapy (CT) with epirubicin-cyclophosphamide (4 courses) followed by docetaxel ± trastuzumab (T) (4 courses). A complete pathological response (pCR) was defined by the absence of residual invasive carcinoma in the breast and axillary lymph nodes. A tissue microarray was constructed from paraffin-embedded tumor samples collected prior to neoadjuvant chemotherapy. Patients' tumours were scored HER2 3+ immunohistochemically (IHC) or 2+ IHC with HER2 amplification by FISH. Immunohistochemical analysis of pMAPK, pAKT, p27 and IGF-IR was performed on tumor tissue microarrays before CT. The H-score (intensity × %) was evaluated. Specimens were classified as exhibiting high or low expression based on a median value as the cut-off point for each marker. A logistic regression model, including the marker and its interaction with treatment, was used to analyse the markers predictive of a treatment effect on the pCR. The independent predictive value was analysed in a multivariate logistic regression adjusting on the lymph node and ER status. Results: 117/120 (97.5%) patients had sufficient tumor for the analysis. The pCR rate was 19% in the CT arm and 25% in the CT+T arm. The median H-score was: pMAPK = 28, pAKT= 25, p27= 50 and IGF-IR = 15. No significant difference was observed in the pCR rate between the two arms according to pAKT, p27, IGF-IR expression. The pCR rate was higher in CT+T compared to CT alone in patients with high pMAPK expression (OR = 4.7 (0.9–24.2); interaction p = 0.03). No difference was observed in the pCR rate in patients with low pMAPK expression (OR = 0.5 (0.1–1.8). Conclusions: In HER2-positive breast cancers, pMAPK expression evaluated by IHC was significantly associated with a pathological response in the arm with neoadjuvant trastuzumab. High pMAPK expression could be a predictive marker of response to trastuzumab in a CT +T regimen. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-04.

Neutrophil Gelatinase-Associated Lipocalin (NGAL) Predicts Response to Neoadjuvant Chemotherapy and Clinical Outcome in Primary Human Breast Cancer

In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC.

Overexpression of epithelial growth factor receptor (EGFR) predicts better response to neo-adjuvant chemotherapy in patients with triple-negative breast cancer

BackgroundTriple negative breast cancer (TNBC) occurs in approximately 10% to 25% of all patients with breast cancer and is associated with poor prognosis. Neo-adjuvant chemotherapy has been reported to produce a higher pathologic complete response (pCR) rate in TNBC. If pCR is achieved, patients with TNBC had a similar survival with non-TNBC patients. The aim of our study was to investigate the protein expression of epithelial growth factor receptor (EGFR) and response to neo-adjuvant chemotherapy and clinical outcome in patients with TNBC compared with non-TNBC.MethodsA total of 198 locally advanced breast cancer patients who received neo-adjuvant chemotherapy were studied. Immunohistochemistry (IHC) was carried out to detect the protein expression of EGFR in tumor samples. Clinical and pathological parameters, pCR rate and survival data were compared between 40 TNBCs and 158 non-TNBCs.ResultsIn 198 cases who received neo-adjuvant chemotherapy, significant differences exist in surgical therapy (P=0.005) and pCR rate (P=0.012) between patients with TNBCs and non-TNBCs. Overexpression of EGFR was significantly associated with pCR rate in patients with TNBCs (P < 0.001). Survival analysis revealed that patients with TNBCs had worse DFS and OS than those with non-TNBCs (P = 0.001, P < 0.001 respectively). Furthermore, for patients with non-TNBCs, those who acheived pCR had better DFS and OS than those who acheived RD (both P < 0.001).ConclusionsOur results suggested that patients with TNBCs had increased pCR rates compared with non-TNBC. Overexpression of EGFR predicted better response to neo-adjuvant chemotherapy in patients with TNBCs.

Increased efficacy of a dose-dense regimen of neoadjuvant chemotherapy in breast carcinoma: a retrospective analysis

Neoadjuvant chemotherapy is being increasingly used in the treatment of breast carcinoma. We performed a single-center retrospective analysis of the results of neoadjuvant therapy in 376 breast carcinoma patients treated with three different regimens combining doxorubicin and paclitaxel (AT), dose-dense doxorubicin and cyclophosphamide with sequential weekly paclitaxel (DD AC-P), or the combination of trastuzumab with chemotherapy (DD AC-PT). The expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor (HER)-2 was determined immunohistochemically. Pathological response was determined in 318 patients. Pathological complete response (pCR) was observed in 18% of patients. The pCR rate was significantly higher in patients treated with DD regimen (22 vs. 13%) and younger than 55 years (23 vs. 13%). The pCR rate was higher in patients with triple negative (TN) tumors (43%) and tumors over-expressing HER-2 (HER-2+; 28%) compared to patients with ER- or PR-positive tumors not expressing HER-2 (ER/PR+HER-2-; 6%). In patients with TN tumors pCR rate was significantly higher after treatment with DD AC-P compared to AT (61 vs. 22%, p=0.005). pCR was associated with significantly improved relapse-free survival (RFS) and overall survival (OS), but when analysis was performed based on tumor phenotype, the difference was significant only in patients with TN tumors. In multivariate analysis, pCR, stage, and ER expression were significant predictors of RFS, while pCR, stage, ER and DD regimen were significant predictors of OS. In conclusion, present data indicate superiority of a DD regimen in obtaining pCR in patients with breast carcinoma treated with neoadjuvant chemotherapy. The difference in efficacy is due mostly to markedly higher pCR rate in patients with TN tumors.

Efficacy analysis of THP-containing regimens as neoadjuvant and adjuvant chemotherapy for primary breast cancer

To evaluate the effect of anthracycline pirarubicin-based regimen in association with different ways of fluorouracil (5-Fu) as neoadjuvant and adjuvant chemotherapy for primary breast cancer. Two hundred and eighty-nine primary breast cancer patients who were to be operated, two to eight cycles of pirarubicin in association with cyclophosphamide and 5-Fu (CTF or CTFci regimen) were given before operation. The pathological response rate, effect and its relation with the infusion routes of 5-Fu were analyzed. The overall pathological complete remission (pCR) rate was 28.4%. The median follow-up period was 39 months. The 5-year DFS was 87.6% (95% CI:82.1% to 92.7%), 5-year DDFS was 89.9% (95% CI:84.0% to 95.8%), and overall survival was 99.6%. CTFci (5-Fu, continuous infusion) regimen was superior to CTF regimen in pCR rates (32.3% vs. 20.2%, P = 0.037), and 5-year DDFS were 92.9% and 80.1%, respectively (P = 0.015). The pCR group was superior to non-pCR group in 5-year DDFS (92.4% vs. 85.6%, P = 0. 033). The pCR rate of patients with ER/PR-positive tumor was significantly lower than those of ER/PR-negative (P = 0.004). The 5-year DDFS rates of HER-2 (+) and HER-2(-) groups were 75.0% and 91.9%, respectively (P = 0.043). In the ER/PR-positve group, the 5-year DDFS of CTFci regimen was superior to those of CTF regimen, 91.4% vs. 81.4% (P = 0.047). CTF/CTFci regimen as neoadjuvant and adjuvant chemotherapy is effective for primary breast cancer. CTFci regimen is superior to CTF regimen in pathological complete response rate and 5-year DDFS. CTFci regimen may do better to ER/PR (+) patients' benefits compared with CTF regimen.

PD07-04: Lapatinib vs Trastuzumab in Combination with Standard EC-D Chemotherapy in the Neaodjuvant Treatment of HER2+ Patients. Results from the GEICAM 2006–14 Phase II Randomized Trial.

Abstract Background: The addition of trastuzumab (T) to neoadjuvant chemotherapy increases pCR rate in patients with HER2 + breast cancer. Lapatinib (L) in combination with chemotherapy is also an active drug in breast cancer patients. This study investigates the efficacy of trastuzumab or lapatinib added to chemotherapy in the neoadjuvant setting. Methods: Patients (Pt) with tumors greater than 2 cm (or less with positive axilla) and HER2+ (Herceptest 3+ or 2+ with FISH+) that have not received any prior treatment for breast cancer were recruited. Pts were randomized to receive epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 × 4 cycles (cy) followed by docetaxel 100 mg/m2 (with growth colony stimulating factor support) plus either T 8 mg/kg loading dose and then 6 mg/Kg intravenous (EC-DT) or L 1250 mg orally (EC-DL). Patients were stratified according to tumor size (T1-2 vs T3-4), and estrogen receptor status (positive vs negative). The primary end-point was pathological complete response (pCR) in the breast measured by Miller and Payne criteria. Secondary end-points were clinical response (by imaging test), toxicity and correlation between pCR and tumor biomarkers. Results: From February-09 to October-10, 102 pts were randomized (50 EC-DT, 52 EC-DL). Pts characteristics were well balanced between arms. Median age was 48 years (30-79), 56% of pts were premenopausal, 7% grade I, 45% grade III. 14/59/12/15% were T1/T2/T3/T4 and 69% N+. 58% were estrogen receptor positive and 44% progesterone receptor positive. Three patients were FISH negative after central assessment and were not considered evaluable for efficacy. pCR rate in the breast was 52% (95% CI: 38–66) for EC-DT and 25% (95% CI: 13.5−37.5) for EC-DL (p-value=0.0065). pCR—pN0 was 48% (95% CI: 34–62) for EC-DT and 24% (95% CI: 12 - 35) for EC-DL (p-value=0.01). Clinical response was 77% with EC-DT and 65% with EC-DL (p-value=0.176). Grade III-IV toxicity was similar between arms except for diarrhea that was more frequent in EC-DL 14% than in EC-DT 2% (p-value=0.03); more patients discontinue treatment due to toxicity with EC-DL (1 vs 6; p-value=0.055). Conclusions: Our study shows that EC-DT was more efficacious and less toxic than EC-DL in the neoadjuvant treatment of HER2+ pts. Biomarker profiling in the tumors, including activation levels of tyrosine-kinase receptors, signaling pathways and surrogate markers (proliferation and apoptosis) is ongoing; their correlation with pCR will be presented at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-04.

Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience.

To compare the pathologic complete response (pCR) rate and relapse-free survival (RFS) and overall survival (OS) after neoadjuvant systemic chemotherapy (NST) in patients with breast cancer with and without deleterious BRCA1 and BRCA2 mutations. A total of 317 women who underwent BRCA genetic testing and were treated with NST for breast cancer between 1997 and 2009 were included in the study. The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models were fit to determine the associations between BRCA status, pCR, and survival. Fifty-seven (18%) and 23 (7%) patients had BRCA1 and BRCA2 mutations, respectively. Twenty-six (46%) of 57 BRCA1 carriers achieved a pCR, compared with three (13%) of 23 BRCA2 carriers and 53 (22%) of 237 BRCA noncarriers (P < .001). In the multivariate logistic model, BRCA1 status (odds ratio [OR] = 3.16; 95% CI, 1.55 to 6.42; P = .002), estrogen receptor (ER) negativity (OR = 1.96; 95% CI:1.05 to 3.65; P = .03) and concurrent trastuzumab use (OR = 4.18; 95% CI, 2.04 to 8.57; P < .001) remained as independent significant predictors for a pCR. At a median follow-up of 3.2 years, 69 patients (22%) experienced a disease recurrence or death. No significant differences were noted in survival outcomes with respect to BRCA status and type of NST received. However, among BRCA1 carriers, patients who achieved a pCR had better 5-year RFS (P = .001) and OS (P = .01) rates than patients who did not. BRCA1 status and ER negativity are independently associated with higher pCR rates in patients with breast cancer. Overall prognosis of breast cancer in BRCA carriers is similar to sporadic breast cancers.

Pathological complete remission in patients with oesophagogastric cancer receiving preoperative 5‐fluorouracil, oxaliplatin and docetaxel

The aim of this study was to determine the pathological complete remission (pCR) rate, and its relationship to clinical outcome, in patients with adenocarcinoma of the stomach or oesophagogastric junction receiving preoperative 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) every 2 weeks. Data from these patients who received at least one cycle of preoperative FLOT followed by surgery were prospectively collected in three German centres. Outcome analyses were conducted and tumour samples were evaluated for pathological remission by a central pathologist. A total of 46 patients were included in this analysis. All patients had clinical T3- and/or N+-stages and 11 (23.9%) had distant metastases (M1). After a median of 4 (range 2-8) preoperative cycles, 8 of 46 patients (17.4%) achieved a pCR. The pCR rate was highest in tumours of intestinal type histology (30.8%) and in those located in the oesophagogastric junction (30.4%) and lowest in patients with diffuse/mixed type tumours (0%) or tumours located in the stomach (4.3%; p < 0.05 for both comparisons). Patients with pCR had 100% probability of overall and disease-free survival (DFS) during the observation period, which was significantly higher (p = 0.037 and p = 0.009, respectively) than the survival probability in patients without pCR. In conclusion, treatment intensification using FLOT was associated with significant pCR rates in patients with oesophagogastric cancer. The distribution of pCR appeared to be significantly different according to histological type and location of the tumours.

Pathological complete response rates following different neoadjuvant chemotherapy regimens for operable breast cancer according to ER status, in two parallel, randomized phase II trials with an adaptive study design (ECTO II)

Sequential doxorubicin/paclitaxel (AT) followed by CMF treatment was shown to be an active neoadjuvant chemotherapy regimen in the first European Cooperative Trial in Operable Breast Cancer (ECTO I trial). The aim of the current study (ECTO II) is to assess the complete pathological response (pCR) rate following three different anthracycline and taxane-containing neoadjuvant chemotherapy regimens, with or without capecitabine (X). Patients with operable, invasive breast cancer > 2.0 cm in diameter, were randomized to AT→CMF, AT→CMX or AC→TX regimens in two parallel, randomized, open-label, phase II trials (within a single study) in patients with estrogen receptor negative (ER-) and estrogen receptor positive (ER+) diseases, respectively. Exemestane was delivered concomitantly with neoadjuvant chemotherapy in ER+ tumors. Achievement of pCR was more common in ER- than ER+ women (45.3 vs. 10.4%). Capecitabine was only associated with a higher frequency of pCR in ER+ patients receiving AT→CMX. Overall response rates (ORR) ranged from 88 to 97%, and this translated into high rates of breast-conserving surgery (67% of ER- patients and 72% of ER+ patients). All three regimens were well tolerated. Febrile neutropenia and gastrointestinal effects were the most common grade ≥ 3 adverse events. As expected, the ECTO II study showed higher pCR rates in patients with ER- disease. Substituting capecitabine for fluorouracil (± methotrexate) in anthracycline/taxane-containing regimens appeared to be beneficial only in ER+ tumors. Translational studies investigating interactions between therapeutic agents and tumor biology are warranted to refine patient selection and improve the results of neoadjuvant chemotherapy.