The choice of a neoadjuvant chemotherapy cycle for breast cancer has significance in clinical practice: results from a population-based,real world study

Objective: Neoadjuvant chemotherapy(NAC) is currently used in both early stage and locally advanced breast cancers. The survival benefits of standard vs. non-standard NAC cycles are still unclear. This study aimed to investigate the relationship between NAC cycles and survival based on real world data.Methods: We identified patients diagnosed with invasive primary breast cancers who underwent NAC followed by surgery. Patients who received at least 4 NAC cycles were defined as having received sta...     

Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil,epirubicin and cyclophosphamide,for women with HER2 negative early breast cancer: ARTemis Trial

BackgroundThe ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review.Patients and methodsPatients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class.ResultsA total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2–4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89–1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90–1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23–0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24–0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group.ConclusionsThe addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer.ClinicalTrials.gov numberNCT01093235.     

Platelet/Lymphocyte Ratio Is Superior to Neutrophil/Lymphocyte Ratio as a Predictor of Chemotherapy Response and Disease-free Survival in Luminal B-like (HER2−) Breast Cancer

BackgroundThe neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) have been associated with the prognosis in breast cancer (BC). The relationship of the NLR and PLR with chemotherapy sensitivity and prognosis in luminal B-like (human epidermal growth factor receptor 2-negative [HER2⁻]) BC are not well studied.Patients and MethodsThe clinical data from 980 patients with luminal B-like (HER2⁻) BC from June 2012 to June 2016 were collected. The differences among the variables were calculated using the χ² test. The associations among the clinicopathologic factors, pretreatment NLR, pretreatment PLR, and disease-free survival (DFS) were analyzed using Kaplan-Meier curves and Cox analyses.ResultsThe median follow-up was 37 months (range, 5-77 months). For the 480 patients who had received neoadjuvant chemotherapy, low pretreatment PLR values were associated with higher pathologic complete response (pCR) rates compared with the high PLR group (15.8% for low vs. 9.2% for high PLR group; P = .027). Multivariate analyses showed that larger tumors, a greater number of lymph nodes involved, a high Ki-67 score, and a high PLR were independent prognostic factors of worse outcomes for the patients with luminal B-like (HER2⁻) BC. The risk of metastasis and/or recurrence was greater for the high PLR group than for the low PLR group (hazard ratio, 1.576; 95% confidence interval, 1.039-2.390; P = .032). The pretreatment NLR showed no such associations among this cohort of patients.ConclusionsThe results of the present study have shown that the pretreatment PLR is superior to the NLR as a predictor of pCR and DFS outcomes in patients with luminal B-like (HER2⁻) BC. A low pretreatment PLR was associated with higher pCR rates after neoadjuvant chemotherapy and was an independent predictive factor for better DFS outcomes among patients with luminal B-like (HER2⁻) BC.     

Long-term outcome of the REMAGUS 02 trial,a multicenter randomised phase II trial in locally advanced breast cancer patients treated with neoadjuvant chemotherapy with or without celecoxib or trastuzumab according to HER2 status

BackgroundThe REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS).Patients and methodsFrom 2004 to 2007, 340 stage II–III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin–cyclophosphamide followed by four cycles of docetaxel) +/− celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106).ResultsMedian follow-up was nearly 8 years (94.4 months, 20–127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2–0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36–0.92], p = 0.021).ConclusionCelecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC.     

Effects of Adjuvant Chemotherapy on Locally Advanced Upper Tract Urothelial Carcinoma: A Systematic Review and Meta-analysis

IntroductionWe aimed to perform a systematic review and meta-analysis to evaluate the current role of adjuvant chemotherapy (ACH) after radical nephroureterectomy (RNU) in patients with locally advanced upper tract urothelial carcinoma (UTUC).Materials and MethodsThe PubMed/MEDLINE, EMBASE, and Cochrane Library databases were searched for relevant studies in English from January 1980 to April 2019. The inclusion criteria was determined based on the population, intervention, comparator, outcome, and study design. The endpoints were disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) of each endpoint were extracted from the included studies.ResultsA total of 11 studies were included in the final analysis to investigate the role of ACH in locally advanced UTUC. Overall, 798 patients received ACH after RNU, and 1496 patients underwent RNU alone. The pooled HRs for DFS, CSS, and OS among the studies were 0.59 (95% CI, 0.43-0.81; P = .001), 0.73 (95% CI, 0.55-0.95; P = .02), and 0.84 (95% CI, 0.59-1.19; P = .32), respectively. The quality of evidence of each outcome determined by the Grading of Recommendations, Assessments, Developments, and Evaluation approach was low for 2 outcomes and very low for the other outcome.ConclusionsACH following RNU may improve DFS and CSS in patients with locally advanced UTUC. When comparing previously reported meta-analysis of all UTUC patients, the beneficial effects of ACH on CSS might be more pronounced in patients with locally advanced UTUC.     

A Randomized Parallel Controlled Phase II Trial of Recombinant Human Endostatin Added to Neoadjuvant Chemotherapy for Stage III Breast Cancer

BackgroundTo explore the potential advantage of preoperative anti-angiogenosis therapy, we implemented a study to evaluate the efficacy of recombinant human endostatin (EN) in combination with neoadjuvant chemotherapy in the treatment of stage III breast cancer.Patients and MethodsEighty-seven patients were randomized to neoadjuvant TEC (docetaxel, epirubicin, and cyclophosphamide) or to EN+TEC, followed by surgery. The primary endpoint was the objective response rate (ORR). Secondary endpoints included pathologic complete response (pCR), relapse-free survival (RFS), overall survival (OS), and safety.ResultsPatients receiving EN+TEC achieved significantly higher ORR (81.82%; 36/44) compared with those receiving TEC (58.14%; 25/43; P=0.016). There was a non-significant trend of increased pCR with EN treatment (15.91% vs. 6.98%). The median follow-up was 54 months and revealed a significantly higher RFS with EN+TEC (median, 67.3 months; 95% confidence interval [CI], 61.0-73.7 months), compared with TEC (median, 55.0 months; 95% CI, 48.3-61.7 months; P =0.014). EN+TEC also significantly improved OS (74.2 months; 95% CI, 68.9-79.6 months), compared with TEC (59.1 months; 95% CI, 52.0-66.1 months; P =0 .006). The 3- and 5-year OS rates are estimated to be 88.5% and 82.8% with EN+TEC and 76.7% and 54.4% with TEC, respectively. Cox proportional regression analyses showed that EN+TEC was associated with improved OS (hazard ratio, 0.377; 95% CI, 0.418-0.959; P =0 .041). There was no significant difference in adverse events between EN+TEC and TEC.ConclusionThe combination of EN+TEC neoadjuvant chemotherapy significantly improved the ORR and OS, suggesting a benefit of adding anti-angiogenesis to standard chemotherapy in the treatment of locally advanced breast cancer.     

Relationship Between the Neutrophil to Lymphocyte Ratio,Stromal Tumor-infiltrating Lymphocytes,and the Prognosis and Response to Neoadjuvant Chemotherapy in Triple-negative Breast Cancer

IntroductionNeutrophil to lymphocyte ratio (NLR) and stromal tumor-infiltrating lymphocytes (sTILs) are correlated with triple-negative breast cancer (TNBC) patient prognosis. However, there has been insufficient research regarding the relationship between systemic and local inflammatory states in patients with TNBC, and their effects on neoadjuvant chemotherapy (NAC) efficacy.MethodsThe clinical data of 395 patients with TNBC admitted from January 2010 to December 2018 were collected. The Pearson χ² test was used to analyze correlations between clinical basic pathological features, NLR, sTILs, and pathological complete response (pCR). Kaplan-Meier and Cox analyses were performed to address which clinical parameters were prognostic factors of disease-free survival (DFS).ResultsThere was no correlation between NLR1 (baseline NLR) and sTILs (P > .05) in these patients with TNBC. Patients with TNBC with lower NLR3 (baseline NLR of patients receiving NAC) or higher sTILs scores had better pCR rates, but this failed to reach statistical significance (P > .05). Cox analysis showed that NLR1 and sTILs were independent prognostic indicators of DFS outcome in patients with TNBC (P < .01).ConclusionIn patients with TNBC, low NLR1 and high sTILs are associated with prolonged DFS. However, the link between systemic and local inflammation markers needs further exploration.     

Combined detection of preoperative neutrophil to lymphocyte ratio and interleukin-6 as an independent prognostic factor for patients with non-metastatic colorectal cancer

BackgroundThis study sought to explore the value of the neutrophil to lymphocyte ratio (NLR) and interleukin-6 (IL-6) in predicting the prognosis of patients with non-metastatic colorectal cancer (CRC).MethodsThe data of 88 surgical CRC patients were retrospectively analyzed. A receiver operating characteristic (ROC) curve analysis was conducted to determine the patients’ thresholds for the NLR and IL-6. Kaplan-Meier curve and Cox regression models were used to assess the prognostic values.ResultsA ROC analysis was conducted to calculate the NLR cut-off value. The area under the curve (AUC) of the NLR was 0.739 [95% confidence interval (CI): 0.634 to 0.844] for overall survival (OS), and 0.799 (95% CI: 0.705 to 0.892) for disease-free survival (DFS). The AUC of IL-6 was 0.773 (95% CI: 0.670 to 0.876) for OS, and 0.817 (95% CI: 0.728 to 0.906) for DFS. The AUC of NLR + IL-6 was 0.805 (95% CI: 0.710 to 0.899) for OS and 0.853 (95% CI: 0.774 to 0.933) for DFS, which were higher than the NLR or IL-6 alone AUCs for OS and DFS. In addition, a high NLR and IL-6 value was significantly correlated with tumor differentiation and tumor-node-metastasis staging. The NLR was positively correlated with IL-6 level (r=0.481). The results of the Kaplan-Meier analysis showed that a high NLR + IL-6 value was correlated with worse OS and DFS.ConclusionsA high NLR and IL-6 value is a better independent prognostic biomarker of CRC than the NLR or IL-6 level alone, and may be applied in clinical practice to identify high-risk patients.     

Neutrophil-to-Lymphocyte Ratio Predicts Cancer Outcome in Locally Advanced Clear Renal Cell Carcinoma

BackgroundTo evaluate the association of neutrophil-to-lymphocyte ratio (NLR) with recurrence-free survival (RFS) and overall survival (OS) in patients with locally advanced nonmetastatic clear cell renal cell carcinoma (ccRCC) undergoing radical nephrectomy.Material and MethodsWe retrospectively identified 880 nephrectomies performed between January 2009 and December 2016 in a single center, reviewed data from 478 radical nephrectomies for kidney tumors and identified 187 patients with locally advanced nonmetastatic ccRCC (pT3-T4 N0M0). NLR was obtained preoperatively and calculated by dividing absolute neutrophil count by absolute lymphocyte count. OS and RFS were evaluated by the Kaplan–Meier method. Cox proportional-hazards regression models were used to evaluate predictors of RFS and OS.ResultsAmong 187 patients with ccRCC (mean age 63.4 ± 11.5 years; 118 [63.1%] male), the median follow-up was 48.7 months. On univariate analysis, in patients with Fuhrman nuclear grade of differentiation 3-4, the median time to recurrence was significantly shorter with NLR ≥ 4 than < 4 (24 vs. 55 months, P = .045). On multivariable analysis adjusted for NLR ≥ 4, among all variables analyzed (NLR, microvascular invasion, sarcomatoid differentiation, tumor size and body mass index), only nuclear grade of differentiation was an independent predictor of recurrence (hazard ratio 2.18; 95% confidence interval 1.07-4.92, P = .03). The 3-year OS had no statistically significant difference between patients with NLR ≥ 4 or < 4.ConclusionFor patients with locally advanced, nonmetastatic ccRCC, RFS was reduced with high nuclear grade of differentiation and high preoperative NLR. These findings suggest an association between higher NLR and worse outcomes in locally advanced ccRCC.     

Prognostic and predictive value of neutrophil-to-lymphocyte ratio after curative rectal cancer resection: A systematic review and meta-analysis

BackgroundNeutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with poor prognosis in numerous solid malignancies. Here, we quantify the prognostic value of NLR in rectal cancer patients undergoing curative-intent surgery, and compare it with platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR).MethodsA comprehensive search of several electronic databases was performed through January 2021, to identify studies evaluating the prognostic impact of pretreatment NLR in patients undergoing curative rectal cancer resection. The endpoints were overall survival (OS), disease-free survival (DFS), and clinicopathologic parameters. The pooled hazard ratio (HR) or odds ratio with 95% confidence interval (CI) were calculated.ResultsThirty-one studies comprising 7553 patients were assessed. All studies evaluated NLR; thirteen and six evaluated PLR and LMR, respectively. High NLR was associated with worse OS (HR 1.92, 95% CI 1.60–2.30, P < 0.001) and DFS (HR 1.83, 95% CI 1.51–2.22, P < 0.001), and the results were consistent in all subgroup analyses by treatment modality, tumor stage, study location, and NLR cut-off value, except for the subgroups limited to cohorts with cut-off value ≥ 4. The size of effect of NLR on OS and DFS was greater than that of PLR, and similar to that of LMR. Finally, high NLR was associated with lower rate of pathologic complete response.ConclusionsIn the setting of curative rectal cancer resection, pretreatment NLR correlates with tumor response to neoadjuvant therapy, and along with LMR, is a robust predictor of poorer prognosis. These biomarkers may thus help risk-stratify patients for individualized treatments and enhanced surveillance.     

Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy

BackgroundThe aim of this study was to evaluate the impact of pathologic complete response (pCR) on outcome in patients with gastric or esophagogastric junction (EGJ) adenocarcinoma after neoadjuvant docetaxel/platin/fluoropyrimidine-based chemotherapy.Patients and methodsPatients received at least one cycle of chemotherapy for potentially operable disease. Pretreatment clinicopathologic factors and pCR were investigated. Disease-free survival (DFS), overall survival (OS) and tumor-related death were correlated with pCR.ResultsOne hundred twenty patients were included in this analysis. Eighteen patients (15%) achieved a pCR. Tumor localization in the EGJ was identified as the only significant predictor of pCR (P = 0.019). Median follow-up was 41.1 months. Median DFS and OS for all patients were 24.1 and 48.6 months, respectively. Median DFS for patients with a pCR was not reached versus 22.1 months non-pCR patients (hazard ratio, HR 0.38; 3-year DFS: 71.8% and 37.7%, respectively, P = 0.018). While OS was not significantly different, the risk for tumor-related death was significantly lower for pCR patients compared with non-pCR patients (3-year cumulative incidences of 6.4% and 45.4%, respectively, P = 0.009).ConclusionA pCR following preoperative docetaxel/platin/fluoropyrimidine indicates favorable outcome in patients with gastric or EGJ adenocarcinoma. Tumor location in the EGJ is associated with a higher pCR rate.     

Down-staging depth score could be a survival predictor for locally advanced gastric cancer patients after preoperative chemoradiotherapy

ObjectiveThe predictive effect of preoperative chemoradiotherapy (CRT) is low and difficult in guiding individualized treatment. We examined a surrogate endpoint for long-term outcomes in locally advanced gastric cancer patients after preoperative CRT.MethodsFrom April 2012 to April 2019, 95 patients with locally advanced gastric cancer who received preoperative concurrent CRT and who were enrolled in three prospective studies were included. All patients were stage T_3/4N₊. Local control, distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were evaluated. Clinicopathological factors related to long-term prognosis were analyzed using univariate and multivariate analyses. The down-staging depth score (DDS), which is a novel method of evaluating CRT response, was used to predict long-term outcomes. ResultsThe median follow-up period for survivors was 30 months. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve predicted by the DDS was 0.728, which was better than the pathological complete response (pCR), histological response and ypN0. Decision curve analysis further affirmed that DDS had the largest net benefit. The DDS cut-off value was 4. pCR and ypN0 were associated with OS (P=0.026 and 0.049). Surgery and DDS are correlated with DMFS, DFS and OS (surgery: P=0.001, <0.001 and <0.001, respectively; and DDS: P=0.009, 0.013 and 0.032, respectively). Multivariate analysis showed that DDS was an independent prognostic factor of DFS (P=0.021).ConclusionsDDS is a simple, short-term indicator that was a better surrogate endpoint than pCR, histological response and ypN0 for DFS.     

Preoperative Intensity-modulated Chemoradiotherapy with Simultaneous Integrated Boost in Rectal Cancer: Five-year Follow-up Results of a Phase II Study

BackgroundWe conducted a phase II study to investigate the feasibility and safety of preoperative radiochemo-therapy experimental fractionation, using intensity-modulated radiation therapy with simultaneous integrated boost (IMRT SIB) to shorten the overall treatment time without dose escalation in intermediate/locally advanced rectal cancer with the aim to improving treatment outcome.Patients and methodsA total of 51 patients with operable stage II–III rectal carcinoma were included between January 2014 and January 2015. Fifty patients completed preoperative IMRT treatment with an elective dose of 41.8 Gy and simultaneously delivered 46.2 Gy to T2/T3 and 48.4 Gy to T4 tumour in 22 fractions, with concomitant capecitabine (825 mg/m2/12 h, including at weekends). Median follow-up was 70 months (range 11–80 m).ResultsForty-seven patients completed treatment per protocol. Acute toxicity occurred in 2 (4%) patients. R0 resection was achieved in all but 1 and pathologic complete response (pCR) in 12 (25.5%) patients who had 5-year overall survival (OS), disease-free survival (DFS) and local control (LC) of 91.7%, 100% and 100%, respectively. The intention-to-treat analysis showed that the type of surgery significantly moderated OS and DFS, while total downstaging and pN were predictive for DFS only. For treatment per protocol 5-year OS, DFS and LC were 80.9% (95% confidence interval [CI] 69.7–92.1), 77.1% (95% CI 65.1–89.1) and 95.2% (95% CI 88.7–100), respectively. The proportion of patients with severe late (CTCAE G ≥ 3) gastrointestinal, urinary and sexual toxicity was 15%, 2% and 8% respectively, with one reported secondary carcinoma.ConclusionsPreoperative IMRT-SIB without dose escalation was well tolerated, with a low acute toxicity profile, we achieved a high rate of pCR and showed encouraging 5-year OS, DFS and LC.Key words: rectal cancer, IMRT, simultaneous integrated boost, preoperative radiochemotherapy, acute toxicity, pathologic complete response, overall survival, disease-free survival, local control, late toxicity, quality of life     

Final results of the CAVE trial in RAS wild type metastatic colorectal cancer patients treated with cetuximab plus avelumab as rechallenge therapy: Neutrophil to lymphocyte ratio predicts survival

BackgroundHigh neutrophil-to-lymphocyte ratio (NLR) is a poor prognostic factor in metastatic colorectal cancer (mCRC). Here we provide final results of CAVE mCRC trial, of cetuximab plus avelumab rechallenge in chemo-refractory mCRC patients and investigated the predictive role of NLR.MethodsAll the 77 patients enrolled were included in the analysis. A cut-off of 3 was used to correlate baseline NLR with with overall survival (OS) and with progression free survival (PFS), in intention to treat (ITT) and in circulating tumor DNA (ctDNA) RAS/BRAF Wild Type (WT) patients.ResultsIn ITT population, NLR <3 (49%) group had median overall survival (mOS) of 17.8 months, vs. 8.9 months in NLR ≥ 3 group (51%) [HR 0.50, (CI 95% 0.3-0.8), P = .006]. Median progression free survival (mPFS) was 3.9 months in NLR <3 group and 3.5 months in NLR≥3 [HR 0.79, (CI 95% 0.5-1.24), P = .3]. In ctDNA RAS/BRAF WT population, mOS was 22 months in NLR <3 group (48%), vs. 8.9 months in NLR ≥3 group (52%), [HR 0.38, (CI 95% 0.19-0.75), P = .005]. A trend towards increased mPFS was observed in patients with NLR <3 versus NLR ≥3: 5.3 vs. 3.6 months [HR: 0.79, (CI 95% 0.44-1.4), P = .43]. In contrast, NLR did not correlate either with PFS or OS in ctDNA RAS/BRAF mutated patients.ConclusionIn the exploratory analysis of the CAVE mCRC trial, baseline NLR <3 significantly correlated with improved survival and may represent a potential predictive biomarker of cetuximab plus avelumab rechallenge activity in ctDNA RAS/BRAF WT patients, that must be confirmed in randomized studies.     

Evaluation of the Predictive and Prognostic Values of Stromal Tumor-Infiltrating Lymphocytes in HER2-Positive Breast Cancers treated with neoadjuvant chemotherapy

Background

Stromal tumor-infiltrating lymphocytes (sTILs) have been identified as a predictive biomarker for response to neoadjuvant chemotherapy (NAC) and prognosis in human epidermal growth factor receptor 2 (HER2)-positive breast cancers. However, standardized scoring methods for use in clinical practice need to be established, and the optimal threshold of sTILs to predict pathological complete response (pCR) and prognosis in HER2+ breast cancers has not yet been defined.

Objective

The predictive and prognostic values of sTILs in patients with HER2-positive breast cancer treated with NAC were evaluated, with the aim to explore the optimal thresholds of sTILs and to investigate the feasibility of scoring methods in clinical practice.

Patients and Methods

A total of 143 core needle biopsy specimens of HER2-positive invasive breast cancers obtained from Chinese patients who had been treated with trastuzumab-based NAC followed by surgery between 2009 and 2015 were extracted from the pathology database of Fudan University Shanghai Cancer Center. sTIL levels in the pre-NAC core needle biopsy specimens were scored using methods recommended by the International TILs Working Group 2014. The associations between sTILs and pCR, disease-free survival (DFS), and overall survival (OS) were evaluated, and the optimal thresholds for predictive and prognostic values of sTILs were analyzed.

Results

First, sTILs were associated with a higher pCR rate in HER2-positive breast cancers. Univariate (per 10% sTILs: odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02–1.08, p?=?0.001) and multivariate regression analyses (per 10% sTILs: OR 1.04, 95% CI 1.00–1.07, p?=?0.034) indicated that sTILs as a continuous variable were a significant predictor of pCR in HER2-positive breast cancers. Receiver operating characteristics (ROC) curve analysis showed that a 20% threshold best distinguished the pCR subgroup from the non-pCR subgroup. The dichotomized sTILs with a threshold set at 20% was a strong predictor of pCR in the univariate (OR 0.25, 95% CI 0.12–0.52, p?<?0.001) and multivariate analyses (OR 0.35, 95% CI 0.14–0.87, p?=?0.024). Second, sTILs were associated with better prognosis in HER2-positive breast cancers. Univariate (DFS: hazard ratio [HR] 0.91, 95% CI 0.88–0.95, p?<?0.001; OS: HR 0.88, 95% CI 0.83–0.94, p?<?0.001), and multivariate analyses (DFS: HR 0.93, 95% CI 0.90–0.97, p?<?0.001; OS: HR 0.92, 95% CI 0.86–0.98, p?=?0.009) suggested that sTILs as a continuous variable had a strong predictive value for improved DFS and OS. As a binary variable with a threshold of 20%, univariate (DFS: HR 6.60, 95% CI 2.91–14.95, p?<?0.001; OS: HR 10.29, 95% CI 2.37–44.66, p?=?0.002) and multivariate analyses (DFS: HR 3.87, 95% CI 1.65–9.12, p?=?0.002; OS: HR 4.74, 95% CI 1.02–22.01, p?=?0.047) indicated that patients with ≥ 20% sTILs had a significantly better prognosis than the patients with < 20% sTILs.

Conclusions

Our study indicates that baseline sTILs scored by methods recommended by the International TILs Working Group in pre-NAC core needle biopsy specimens are significantly correlated with pCR and prognosis in HER2-positive breast cancers. A 20% threshold for sTILs may be a feasible diagnostic marker to predict pCR to NAC and prognosis in patients with HER2-positive breast cancers.

     

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

Background:

Trastuzumab was introduced a decade ago and has improved outcomes for HER2-positive breast cancer. We investigated the factors predictive of pathological complete response (pCR), prognostic factors for disease-free survival (DFS), and interactions between pCR and DFS after neoadjuvant treatment.

Methods:

We identified 287 patients with primary HER2-positive breast cancers given neoadjuvant chemotherapy (NAC) between 2002 and 2011. Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were performed.

Results:

pCR rates differed between patients receiving neoadjuvant trastuzumab treatment or not (47.7% versus 19.3%, P<0.0001). DFS also differed significantly between patients receiving adjuvant trastuzumab or not (hazard ratio=4.84, 95% CI (2.52; 9.31), P<0.001). We analysed 199 patients given neoadjuvant and adjuvant trastuzumab. Multivariate analysis identified older age and hormone receptor-negative tumours as independent predictors of pCR. T stage (hazard ratio=2.55, 95% CI (1.01; 6.48), P=0.05) and strict pCR (hazard ratio=9.15, 95% CI (1.22; 68.83), P=0.03) were independent predictors of DFS. The latter association was significant in the HR-negative subgroup (P=0.02) but not in the HR-positive subgroup (P=0.12).

Conclusions:

Major pCR and DFS gains in HER2-positive BC were observed since ‘trastuzumab'' era. Further improvements rely on the enrollment of accurately selected patients into clinical trials.     

Association Between Perioperative Chemotherapy and Survival in Men Undergoing Radical Resection for Primary Urethral Urothelial Carcinoma: An Analysis of the National Cancer Database

IntroductionThe treatment landscape in invasive primary carcinoma of the urethra of urothelial histology closely aligns that of locally advanced urothelial carcinoma of the bladder. The survival benefit of perioperative chemotherapy for men undergoing radical surgery for primary urethral urothelial carcinoma (UUC) has not yet been well-elucidated.Patients and MethodsUsing the National Cancer Database (NCDB), we identified men diagnosed with non-metastatic invasive UUC (T2-4 N0-2 M0) from 2004 to 2016 treated with radical extirpative surgery. We compared OS between patients who had received peri-operative neoadjuvant (NAC) or adjuvant (AC) chemotherapy and those who had not using Kaplan-Meier curves and multivariable Cox proportional hazards regression model.ResultsA total of 191 patients met inclusion criteria. 113 patients (59.2%) did not receive chemotherapy, while 39 (20.4%) and 39 (20.4%) received NAC and AC, respectively. Median follow-up was 28.0 months. Upon multivariable analysis, receipt of NAC (HR 0.50, 95% CI 0.28-0.91, P = .02) decreased the risk of all-cause mortality, while receipt of AC (HR 0.76, 95% CI 0.41-1.41) was not significantly associated with an OS benefit, as compared to no chemotherapy.ConclusionOur study is the first to evaluate treatment specific outcomes in male patients with primary carcinoma of the urethra. We observed that neoadjuvant chemotherapy in men with UUC was associated with OS benefit. The utilization of NAC may improve survival, consistent with urothelial carcinoma of the bladder.     

Mucinous Adenocarcinoma Predicts Poor Response and Prognosis in Patients With Locally Advanced Rectal Cancer: A Pooled Analysis of Individual Participant Data From 3 Prospective Studies

PurposeTo evaluate the predictive implications and prognosis of mucinous adenocarcinoma (MAC) in locally advanced rectal cancer (LARC) with intensified neoadjuvant treatment.MethodsIndividual patient data of LARC patients from 3 prospective clinical trials was analyzed. Neoadjuvant treatment regimens comprised chemoradiotherapy (CRT) with fluorouracil (5-FU) or mFOLFOX6, neoadjuvant chemotherapy alone with mFOLFOX6 or mFOLFOXIRI. The postoperative pathological result, local recurrence and disease-free survival (DFS) were retrospectively analyzed in patients with MAC and adenocarcinoma (AC) with neoadjuvant treatment.ResultsTotally, 743 patients were recruited, with 620 patients eligible for analysis. Fifty-three (8.5%) patients were MAC. The pathological complete response (pCR) rate and tumor downstaging rate (ypStage 0-I) between MAC and AC patients was 7.5% vs. 22.0% (P = .01) and 20.8% vs. 48.7% (P < .001), respectively. Among patients receiving preoperative CRT with 5FU or mFOLFOX6, the pCR rate and tumor downstaging rate between MAC and AC patients was 11.1% vs. 27.3% (P = .03) and 23.7% vs. 52.6% (P = .001), respectively. Regarding neoadjuvant chemotherapy alone with mFOLFOX6 or mFOLFOXIRI, the pCR rate and tumor downstaging rate was 0 vs.13.2% (P = .11) and 11.8% vs. 42.5% (P = .03) between MAC and AC group, respectively. With the median follow-up time of 38.9 months, the 3-year DFS and 3-year locoregional recurrence rate was 58.4% vs. 77.6% (P = .02) and 26.0% vs. 5.7% (P = .001) in the MAC and AC group, respectively. MAC (hazard ratio [HR] 1.85, 95% confidence interval [CI], 1.15-2.98), PNI (HR 3.23, 95% CI, 1.85-5.72) and LVI (HR 2.04, 95% CI, 1.02-4.08) were independent prognosis factors and were associated with worse DFS.ConclusionsPatients with MAC of the rectum are associated with a lower pCR rate and tumor downstaging rate, higher incidence of local recurrence, and poorer DFS with neoadjuvant treatment.     

Prediction of pathologic complete response to neoadjuvant chemotherapy using machine learning models in patients with breast cancer

Background

The aim of this study was to develop a machine learning (ML) based model to accurately predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) using pretreatment clinical and pathological characteristics of electronic medical record (EMR) data in breast cancer (BC).

Methods

The EMR data from patients diagnosed with early and locally advanced BC and who received NAC followed by curative surgery were reviewed. A total of 16 clinical and pathological characteristics was selected to develop ML model. We practiced six ML models using default settings for multivariate analysis with extracted variables.

Results

In total, 2065 patients were included in this analysis. Overall, 30.6% (n?=?632) of patients achieved pCR. Among six ML models, the LightGBM had the highest area under the curve (AUC) for pCR prediction. After hyper-parameter tuning with Bayesian optimization, AUC was 0.810. Performance of pCR prediction models in different histology-based subtypes was compared. The AUC was highest in HR+HER2- subgroup and lowest in HR?/HER2- subgroup (HR+/HER2- 0.841, HR+/HER2+?0.716, HR?/HER2 0.753, HR?/HER2- 0.653).

Conclusions

A ML based pCR prediction model using pre-treatment clinical and pathological characteristics provided useful information to predict pCR during NAC. This prediction model would help to determine treatment strategy in patients with BC planned NAC.

     

Prognostic Significance of Total Lymphocyte Count,Neutrophil-to-lymphocyte Ratio,and Platelet-to-lymphocyte Ratio in Limited-stage Small-cell Lung Cancer

BackgroundWe sought reliable markers of survival and disease control among patients treated for limited-stage small-cell lung cancer (LS-SCLC).Patients and MethodsSubjects were 122 patients given (chemo)radiotherapy for LS-SCLC at MD Anderson in 2002 through 2015. Pretreatment total lymphocyte count (TLC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were analyzed for associations with overall (OS) and progression-free survival. Optimal cutoff values were identified with receiver operating characteristic curves and survival probabilities with the Kaplan-Meier method.ResultsPretreatment TLC was 1.86 × 10³/μL (±0.88); NLR, 3.44 (±3.69); and PLR, 170.53 (±101.56); corresponding cutoffs were 1.9, 2.9, and 140.1. Higher TLC was associated with superior median and 2-year OS (17.4 vs. 15.7 months and 33% vs. 29%; P = .029), and higher NLR and PLR with worse median and 2-year OS (NLR: 14.9 vs. 17.8 months, 29% vs. 31%; P = .026; PLR: 14.8 vs. 18.9 months, 24% vs. 37%; P = .009). Multivariate Cox regression adjusted for age, disease stage, number of chemotherapy cycles, and use of prophylactic cranial irradiation confirmed the links between high TLC and superior OS (hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.32-0.94; P = .028) and between high NLR and PLR and inferior OS (NLR: HR, 1.86; 95% CI, 1.15-3.01; P = .011; PLR: HR, 1.72; 95% CI, 1.06-2.82; P = .030).ConclusionsBaseline lymphopenia was an indicator of poor prognosis in patients with LS-SCLC.