Single-Agent Neoadjuvant Immunotherapy With a PD-1 Antibody in Locally Advanced Mismatch Repair-Deficient or Microsatellite Instability-High Colorectal Cancer

BackgroundPD-1 blockade has been recommended as first-line therapy for nonresectable or metastatic mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). However, the safety and efficacy of neoadjuvant PD-1 blockade immunotherapy for locally advanced dMMR/MSI-H CRC remain unclear.Patients and MethodsFrom June 2020 to June 2022, 11 locally advanced dMMR/MSI-H CRC patients treated at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) were enrolled. All patients received 6 sintilimab (Innovent, LTD) injections (200 mg/injection, every 3 weeks) before radical laparoscopic resection. The patient clinical and pathological data were analyzed retrospectively.ResultsdMMR was confirmed by immunohistochemistry for all patients. However, polymerase chain reaction (PCR) or next-generation sequencing confirmed MSI-H for only 90.9% (10/11) of the patients, while 1 patient had microsatellite stable (MSS) disease. After 6 injections of neoadjuvant anti-PD-1 therapy, 90.9% (10/11) of the patients (those confirmed to have dMMR and MSI-H disease) achieved pathological complete response (pCR). The other patient, who achieved major pathological response with residual tumor <1%, had dMMR but MSS disease. No grade 3 or above immunotherapy-related adverse events occurred [Common Terminology Criteria for Adverse Events ; version 5.0]. Overall, 72.7% (8/11) of the patients had grade 1-2 immunotherapy-related adverse events . No operational mortality or complications occurred within 30 days after surgery.ConclusionSingle-agent neoadjuvant PD-1 antibody immunotherapy was safe and effective in locally advanced dMMR/MSI-H CRC. Dual confirmation of MMR and MSI status by immunohistochemistry and next-generation sequencing or PCR is necessary for dMMR/MSI-H CRC patients before immunotherapy. The immunotherapy regimen used in this study deserves further validation in phase II and III clinical studies.     

Complete pathological response after chemotherapy or immune checkpoint inhibitors in deficient MMR metastatic colorectal cancer: Results of a retrospective multicenter study

About 5% of the patients with metastatic colorectal cancers (mCRC) present microsatellite instability (MSI)/deficient mismatch repair system (dMMR). While metastasectomy is known to improve overall and progression-free survival in mCRC, specific results in selected patients with dMMR/MSI mCRC are lacking. Our study aimed to describe metastasectomy results, characterize histological response and evaluate pathological complete response (pCR) rate in patients with dMMR/MSI mCRC. We retrospectively reviewed data from all consecutive patients with dMMR/MSI mCRC who underwent surgical metastasectomy between January 2010 and June 2021 in 17 French centers. Primary outcome was to assess the pCR rate defined by tumor regression grade (TRG) 0. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), and explored TRG as predictive factor for RFS and OS. Among the 88 patients operated, 109 metastasectomies were performed in 81 patients after neoadjuvant treatment [chemotherapy ± targeted therapy (CTT): 69, 85.2%; immunotherapy (ICI): 12, 14.8%], and pCR was achieved in 13 (16.1%) patients. Among the latter, pCR rate were 10.2% in the patients having received CTT (N = 7) and 50.0% in the patients treated with ICI (N = 6). Radiological response did not predict TRG. With a median follow-up of 57.9 (IQR 34.2-81.6) months, median RFS was 20.2 (15.4-not reached) months, median OS was not reached. Major pathological responses (TRG0 + TRG1) were significantly associated with longer RFS (HR 0.12, 95% CI 0.03-0.55; P = .006). The pCR rate of 16.1% achieved with neoadjuvant treatment in patients with dMMR/MSI mCRC is consistent with previously reported rates in pMMR/MSS mCRC. Immunotherapy showed better pCR rate than chemotherapy ± targeted therapy. Further prospective trials are needed to validate immunotherapy as neoadjuvant treatment in resectable/potentially resectable dMMR/MSI mCRC and identify predictive factors for pCR.     

直肠腺癌新辅助放化疗疗效影响因素及病理完全缓解对预后的影响

  目的  探讨直肠腺癌新辅助放化疗（neoadjuvant chemoradiotherapy,NCRT）后病理完全缓解（pathologic complete response,pCR）的影响因素及pCR对生存的影响。  方法  回顾性分析2014年1月至2017年12月郑州大学附属肿瘤医院收治的98例直肠腺癌NCRT患者的临床病理资料,分析临床病理特征与pCR的关系以及pCR对预后的影响。  结果  98例患者NCRT后19例（19.4%）获得pCR。单因素分析显示,术前淋巴结转移情况、治疗前CEA水平、肿瘤大小、肿瘤侵犯肠壁周径程度以及KRAS基因状态与直肠腺癌NCRT后pCR相关。Logistic回归多因素分析显示,治疗前CEA≤5 μg/L（OR=4.095,95%CI:1.131~14.823,P=0.032）和肿瘤侵犯肠壁周径（≤1/2）（OR=3.268,95%CI:1.015~10.527,P=0.047）是影响直肠腺癌NCRT后pCR的独立因素。生存分析显示非pCR患者的3年无病生存率（disease-free survival,DFS）为71.1%,显著低于pCR患者100%（P < 0.05）;两者3年总生存率（overall survival,OS）分别为100%和88.5%,差异无统计学意义（P>0.05）。  结论  治疗前检测CEA以及评估肿瘤侵犯肠壁周径程度有助于预测直肠腺癌NCRT后pCR率,提示两者可作为新辅助放化疗疗效的评价指标,并指导临床进行个体化治疗。与pCR患者相比,非pCR直肠癌患者DFS较短。      

LDH-A negatively regulates dMMR in colorectal cancer

Although immune checkpoint inhibitors (ICIs) have achieved unprecedented success in dMMR tumors, pMMR tumors accounting for 85% of colorectal cancer (CRC) cases remain unresponsive. Lactate dehydrogenase A (LDH-A) is the rate-limiting enzyme that catalyzes the transformation of pyruvate to lactate in the process of glycolysis. We investigated the relationship between LDH-A and dMMR with the purpose of exploring the treatment strategy for pMMR CRC patients. We here show that LDH-A can promote the proliferation of dMMR and pMMR CRC cells by positively regulating MMR proteins both in vitro and in vivo. LDH-A inhibition can improve the efficacy of PD-1 blockade in a pMMR CRC xenograft model. A statistical analysis of 186 CRC specimens showed a significant correlation between LDH-A and dMMR status. Moreover, patients with both low LDH-A expression and dMMR exhibited better disease-free survival compared with patients with other combinations. The close correlation of LDH-A and dMMR may offer a promising therapeutic strategy in which the combination of LDH-A inhibitor and ICIs may improve the clinical benefit for pMMR CRC patients.     

Dynamic breast magnetic resonance imaging: pretreatment prediction of tumor response to neoadjuvant chemotherapy

BackgroundDynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may have the potential of predicting response to neoadjuvant chemotherapy for patients with breast cancer. However, most of these studies focused on evaluating hot-spot characteristics. To thoroughly reflect tumor status, the cold spot and heterogeneity characteristics should also be evaluated.Patients and MethodsDCE-MRIs from 60 patients newly diagnosed with primary invasive breast cancer were reviewed. Kinetic parameters (including cold spot, hot spot, and heterogeneity parameters) derived from DCE-MRI data were used to describe cold spot, hot spot, and heterogeneity features. Patients with a pathologic complete response (pCR) or a ductal carcinoma in situ with microinvasion after chemotherapy were categorized into the pCR group. Pretreatment kinetic parameters in the pCR and non-pCR groups were compared by using univariate tests. Binary logistic regression analysis was used to identify the independent predictors for pCR. The best cutoff value of the independent predictor at pretreatment, with which to differentiate between patients who had a pCR and a non-pCR, was calculated by using receiver operating characteristic curve analysis.ResultsAfter chemotherapy, 10 (16.7%) patients were categorized into the pCR group and 50 (83.3%) into non-pCR group. Multivariate analysis showed that pretreatment washout slope at a cold spot (washout^C) was the only significant and independent predictor of pCR (β = 26.128; P = .005). The best pretreatment washout^C cutoff value with which to differentiate between patients who had pCR and those with non-pCR was 0.0277, which yielded a sensitivity of 80.0% (95% CI, 44.4%-97.5%) and a specificity of 74.0% (95% CI, 59.7%-85.4%).ConclusionWashout^C may be used as a predictor for pCR in patients with breast cancer who undergo neoadjuvant chemotherapy.     

Baseline tumor oxygen saturation correlates with a pathologic complete response in breast cancer patients undergoing neoadjuvant chemotherapy

Tissue hemoglobin oxygen saturation (i.e., oxygenation) is a functional imaging endpoint that can reveal variations in tissue hypoxia, which may be predictive of pathologic response in subjects undergoing neoadjuvant chemotherapy. In this study, we used diffuse optical spectroscopic imaging (DOSI) to measure concentrations of oxyhemoglobin (ctO(2)Hb), deoxy-hemoglobin (ctHHb), total Hb (ctTHb = ctO(2)Hb + ctHHb), and oxygen saturation (stO(2) = ctO(2)Hb/ctTHb) in tumor and contralateral normal tissue from 41 patients with locally advanced primary breast cancer. Measurements were acquired before the start of neoadjuvant chemotherapy. Optically derived parameters were analyzed separately and in combination with clinical biomarkers to evaluate correlations with pathologic response. Discriminant analysis was conducted to determine the ability of optical and clinical biomarkers to classify subjects into response groups. Twelve (28.6%) of 42 tumors achieved pathologic complete response (pCR) and 30 (71.4%) were non-pCR. Tumor measurements in pCR subjects had higher stO(2) levels (median 77.8%) than those in non-pCR individuals (median 72.3%, P = 0.01). There were no significant differences in baseline ctO(2)Hb, ctHHb, and ctTHb between response groups. An optimal tumor oxygenation threshold of stO(2) = 76.7% was determined for pCR versus non-pCR (sensitivity = 75.0%, specificity = 73.3%). Multivariate discriminant analysis combining estrogen receptor staining and stO(2) further improved the classification of pCR versus non-pCR (sensitivity = 100%, specificity = 85.7%). These results show that elevated baseline tumor stO(2) are correlated with a pCR. Noninvasive DOSI scans combined with histopathology subtyping may aid in stratification of individual patients with breast cancer before neoadjuvant chemotherapy. Cancer Res; 72(17); 4318-28. ?2012 AACR.     

直肠癌新辅助放化疗后病理完全缓解的临床因素分析

目的 评估影响直肠癌新辅助放化疗后pCR的临床因素。方法 回顾分析2009—2012年间接受新辅助放化疗随后行根治性手术的116例直肠癌患者临床资料。所有患者术前接受盆腔调强放疗50 Gy分25次,同期氟尿嘧啶为基础化疗,完成治疗休息4~8周后行根治性手术。应用 Logistic法分析影响pCR和非pCR的临床因素。结果 共20例患者经新辅助放化疗后达pCR,pCR率为17.2%。单因素分析表明肿瘤侵犯直肠管腔周径范围达75%以上(全周肿瘤)、治疗前血清CEA水平、T分期、N分期、肛缘距离、分化程度、肿瘤最大直径与直肠癌新辅助放化疗后肿瘤pCR水平相关。多因素分析结果显示全周肿瘤、治疗前血清CEA水平和T分期是影响放化疗后肿瘤pCR预测因素。结论 非全周肿瘤、低CEA水平和早T分期等治疗前临床因素可能是获得pCR的重要决定因素。     

HER2 and response to anthracycline-based neoadjuvant chemotherapy in breast cancer

BackgroundThe predictive role of human epidermal growth factor receptor 2 (HER2) to adjuvant anthracycline-based chemotherapy remains controversial. Here, we investigated the association between HER2 status and pathological response in breast cancer patients who received neoadjuvant anthracycline-based regimens.Patients and methodsWomen (n = 538) with operable primary breast cancer received neoadjuvant anthracycline-based chemotherapy. Pathological complete response (pCR) was defined as no invasive breast tumor cells in breast after completion of neoadjuvant chemotherapy. HER2 status was determined by immunohistochemistry and/or by fluorescence in situ hybridization in core biopsy breast cancer tissue obtained before initiation of neoadjuvant chemotherapy.ResultsIn this cohort of 538 patients, 23.9% of patients achieved a pCR in their breast. HER2-positive tumors had a lower rate of pCR than did HER2-negative tumors (14.7% versus 25.7%, P = 0.013); negative HER2 status remained as an independent favorable predictor of pCR after adjusted for age, estrogen receptor, progesterone receptor, tumor size, chemotherapy cycles, and tumor grade in a multivariate analysis (odds ratio = 3.14; 95% confidence interval = 1.60–6.16, P = 0.001). Furthermore, patients with a pCR had a higher 3-year disease-free survival (DFS) rate than did patients without a pCR (P = 0.007).ConclusionWomen with HER2-negative breast cancers rather than HER2-positive tumors benefit from anthracycline-based neoadjuvant chemotherapy.     

Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response—final results from GeparSixto

BackgroundIn the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD).Patients and methodsPatients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA).ResultsA significantly better DFS (hazard ratio 0.56, 95% CI 0.34–0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26–5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46–9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17–1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P = 0.059).ConclusionsThe addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.     

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.     

Therapy with pembrolizumab in treatment-naïve patients with nonmetastatic,mismatch repair deficient colorectal cancer

Therapy with immune checkpoint inhibitors (ICI) is effective in patients with metastatic mismatch-repair deficient (dMMR) colorectal cancer (CRC); however, data on treatment with neoadjuvant ICI in patients with locally advanced CRC are limited. From March 2019 to June 2020, five Danish oncological centers treated 10 patients with a treatment-naïve dMMR CRC with preoperative pembrolizumab, 9 with a nonmetastatic, unresectable colon cancer and 1 with a locally advanced rectum cancer. All 10 patients were evaluated regularly at a multidisciplinary team (MDT) meeting, and they all had a radical resection after a median of 8 cycles (range 2-13) of pembrolizumab. A microscopic evaluation of the resected tumors revealed no remaining tumor cells in five patients, while five still had tumor cells present. The patients were given no additional therapy. No recurrences were reported after a median follow-up of 26 months (range 23-38.5 months). Biopsies from Danish patients with CRC are routinely screened for dMMR proteins. In 2017, data from the Danish Colorectal Cancer Group showed that 19% (565/3000) of the patients with colon cancer and 1.5% (19/1279) of those with rectum cancer had an dMMR tumor. Among the patients with MMR determination, 26% (99/384) patients had a T4 dMMR colon cancer; thus, the 10 patients treated with neoadjuvant pembrolizumab comprised about 9% of the patients with a T4 dMMR colon cancer (9/99) and 5% of patients with dMMR rectal cancer (1/19). Therapy with pembrolizumab was feasible and effective. Larger prospective trials are needed to confirm our findings.     

Neoadjuvant bevacizumab and anthracycline–taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44)

BackgroundWe evaluated the pathological complete response (pCR) rate after neoadjuvant epirubicin, (E) cyclophosphamide (C) and docetaxel containing chemotherapy with and without the addition of bevacizumab in patients with triple-negative breast cancer (TNBC).Patients and methodsPatients with untreated cT1c-4d TNBC represented a stratified subset of the 1948 participants of the HER2-negative part of the GeparQuinto trial. Patients were randomized to receive four cycles EC (90/600 mg/m²; q3w) followed by four cycles docetaxel (100 mg/m²; q3w) each with or without bevacizumab (15 mg/kg; q3w) added to chemotherapy.ResultsTNBC patients were randomized to chemotherapy without (n = 340) or with bevacizumab (n = 323). pCR (ypT0 ypN0, primary end point) rates were 27.9% without and 39.3% with bevacizumab (P = 0.003). According to other pCR definitions, the addition of bevacizumab increased the pCR rate from 30.9% to 41.8% (ypT0 ypN0/+; P = 0.004), 36.2% to 46.4% (ypT0/is ypN0/+; P = 0.009) and 32.9% to 43.3% (ypT0/is ypN0; P = 0.007). Bevacizumab treatment [OR 1.73, 95% confidence interval (CI) 1.23–2.42; P = 0.002], lower tumor stage (OR 2.38, 95% CI 1.24–4.54; P = 0.009) and grade 3 tumors (OR 1.68, 95% CI 1.14–2.48; P = 0.009) were confirmed as independent predictors of higher pCR in multivariate logistic regression analysis.ConclusionsThe addition of bevacizumab to chemotherapy in TNBC significantly increases pCR rates.     

Outcomes of neoadjuvant chemoradiotherapy followed by radical resection for T4 colorectal cancer

BACKGROUNDPatients with clinical T4 colorectal cancer (CRC) have a poor prognosis because of compromised surgical margins. Neoadjuvant therapy may be effective in downstaging tumors, thereby rendering possible radical resection with clear margins. AIMTo evaluate tumor downsizing and resection with clear margins in T4 CRC patients undergoing neoadjuvant concurrent chemoradiotherapy followed by surgery.METHODSThis study retrospectively included 86 eligible patients with clinical T4 CRC who underwent neoadjuvant concurrent chemoradiotherapy followed by radical resection. Neoadjuvant therapy consisted of radiation therapy at a dose of 45-50.4 Gy and chemotherapy agents, either FOLFOX or capecitabine. A circumferential resection margin (CRM) of < 1 mm was considered to be a positive margin. We defined pathological complete response (pCR) as the absence of any malignant cells in a specimen, including the primary tumor and lymph nodes. A multivariate logistic regression model was used to identify independent predictive factors for pCR.RESULTSFor 86 patients who underwent neoadjuvant chemoradiotherapy and surgery, the rate of pCR was 14%, and the R0 resection rate was 91.9%. Of the 61 patients with rectal cancer, 7 (11.5%) achieved pCR and 5 (8.2%) had positive CRMs. Of the 25 patients with colon cancer, 5 (20%) achieved pCR and 2 (8%) had positive CRMs. We observed that the FOLFOX regimen was an independent predictor of pCR (P = 0.046). After a median follow-up of 47 mo, the estimated 5-year overall survival (OS) and disease-free survival (DFS) rates were 70.8% and 61.4%, respectively. Multivariate analysis revealed that a tumor with a negative resection margin was associated with improved DFS (P = 0.014) and OS (P = 0.001). Patients who achieved pCR exhibited longer DFS (P = 0.042) and OS (P = 0.003) than those who did not.CONCLUSIONNeoadjuvant concurrent chemoradiotherapy engenders favorable pCR and R0 resection rates among patients with T4 CRC. The R0 resection rate and pCR are independent prognostic factors for patients with T4 CRC.     

Association between HER2 status and response to neoadjuvant anthracycline followed by paclitaxel plus carboplatin chemotherapy without trastuzumab in breast cancer

Background

We recently showed HER2-positive breast cancers are less likely to respond to neoadjuvant anthracycline chemotherapy. Here, we investigated whether HER2-positive breast cancers responded to sequential neoadjuvant anthracycline followed by paclitaxel plus carboplatin regimen in the absence of trastuzumab.

Methods

Women (n=372) with operable primary breast cancer initially received two cycles of neoadjuvant anthracyclines, the clinical tumor response was assessed, then patients were received four cycles of paclitaxel plus carboplatin regimen. All the patients did not received trastuzumab treatment in the neoadjuvant setting. HER2 status was determined by immunohistochemistry and/or by fluorescence in situ hybridization in core-biopsy breast cancer tissue obtained before the neoadjuvant chemotherapy.

Results

Eighteen percent (67/372) of patients achieved a pathologic complete response (pCR) in their breast. HER2-positive tumors had a significant higher pCR rate than HER2-negative tumors (33.0% versus 13.5%, P<0.001) in this cohort of 372 patients, and positive HER2 status remained an independent favorable predictor of pCR in a multivariate analysis [odds ratio (OR), 2.26; 95% confidence interval (CI), 1.18 to 4.36, P=0.015]. Furthermore, patients who responded to initial anthracycline regimens were more likely to respond to paclitaxel plus carboplatin than patients who did not (pCR, 27.2% versus 14.6%, P=0.005). Patients with HER2-positive tumors exhibited a significant higher pCR rate than did patients with HER2-negative tumors in both anthracycline response group (40.5% versus 20.0%, P=0.025) and anthracycline non-response group (28.3% versus 11.3%, P=0.002).

Conclusions

Under the circumstance of no trastuzumab treatment, women with HER2-positive cancers derive a large benefit from paclitaxel-carboplatin-based neoadjuvant chemotherapy.     

Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials

Pathological complete response (pCR) to neoadjuvant treatment correlates with outcome in breast cancer. We determined whether characteristics of neoadjuvant therapy are associated with pCR. We used multi-level models, which accounted for heterogeneity in pCR across trials and trial arms, to analyze individual patient data from 3332 women included in 7 German neoadjuvant trials with uniform protocols. PCR was associated with an increase in number of chemotherapy cycles (odds ratio [OR] 1.2 for every two additional cycles; P = 0.009), with higher cumulative anthracycline doses (OR 1.6; P = 0.002), higher cumulative taxane doses (OR 1.6; P = 0.009), and with capecitabine containing regimens (OR 1.62; P = 0.022). Association of pCR with increase in number of cycles appeared more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; P for interaction = 0.046). Effect of anthracycline dose was particularly pronounced in HER2-negative tumors (OR 1.61), compared to HER2-positive tumors (OR 0.83; P for interaction = 0.14). Simultaneous trastuzumab treatment in HER2-positive tumors increased odds of pCR 3.2-fold (P < 0.001). No association of pCR and number of trastuzumab cycles was found (OR 1.20, P = 0.39). Dosing characteristics appear important for successful treatment of breast cancer. Longer treatment, higher cumulative doses of anthracyclines and taxanes, and the addition of capecitabine and trastuzumab are associated with better response. Tailoring according to breast cancer phenotype might be possible: longer treatment in HR-positive tumors, higher cumulative anthracycline doses for HER2-negative tumors, shorter treatment at higher cumulative doses for triple-negative tumors, and limited number of preoperative trastuzumab cycles in HER2-positive tumors.     

体素内不相干运动扩散加权成像在预测局部进展期直肠癌新辅助放化疗疗效中的初步研究

背景与目的：弥散加权成像(diffusion-weighted imaging,DWI)是目前检查活体组织中水分子扩散运动的理想方法,常规DWI使用单指数拟合函数得到表观扩散系数(apparent diffusion coefficient,ADC)值,而体素内不相干运动扩散加权磁共振成像(intravoxel incoherent motion MR imaging,IVIM-MRI)则采用足够多的低b值和高b值并使用双指数拟合函数,可获取更丰富的生物信息,因此本研究欲探讨IVIM-MRI的单、双指数模型在预测局部进展期直肠癌新辅助放化疗疗效中的应用价值。方法：纳入32例接受新辅助放化疗的局部进展期直肠癌并在新辅助治疗前、后行常规MR序列及IVIM序列扫描的患者。IVIM序列包括9个b值(0~800 s/ mm²),所得IVIM序列原始数据经单、双指数模型处理,得到单、双指数模型衰减曲线,并生成对应参数图。测量新辅助治疗前、后肿瘤实质区单指数模型ADC值和双指数模型D值、灌注系数D^*值、灌注分数f值,采用配对样本t检验进行分析;并比较病理完全缓解(pathological complete response,pCR)组和非pCR组新辅助治疗前、后参数差异。组间比较采用两独立样本t检验,P<0.05为差异有统计学意义。结果：IVIM的单指数模型中,治疗前肿瘤平均ADC值［(133.2±21.5)×10^-5 mm/s］较治疗后［(166.9±29.7)×10^-5 mm/s］小且差异有统计学意义(P<0.05);双指数模型中,新辅助放化疗前pCR组肿瘤D*值［(4 471±1 271)×10^-5 mm/ s］低于非pCR组［(5 749±1 722)×10^-5mm/s］,差异有统计学意义(P<0.05);新辅助放化疗后pCR组肿瘤D值［(97.0±14.6)×10^-5 mm/s］低于非pCR组［(113.4±22.6)×10^-5 mm/s］,且差异有统计学意义(P<0.05)。结论：基于常规DWI序列,IVIM双指数模型可更加详细补充描述肿瘤扩散信息。     

Impact of Institutional Universal Microsatellite-Instability (MSI) Reflex Testing on Molecular Profiling Differences Between Younger and Older Patients with Colorectal Cancer

IntroductionDNA mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC) is found in about 15% of early-stage diseases and 5% of metastatic diseases. We reviewed a large, single-institutional database after implementation of universal reflex dMMR/MSI-H testing in CRC to compare profiles of younger (≤50) and older (>50) patients.Patients and MethodsBetween 2009 and 2017, all patients diagnosed with CRC at the University of Florida underwent reflex somatic tumor testing for dMMR by immunohistochemistry (MLH1, PMS2, MSH2, MSH6), MSI by PCR, and Next-Generation Sequencing. Statistical analysis was conducted with 2-sample comparison tests and logistic regression models.ResultsThere were 375 patients included in the final analysis. Patients were grouped as younger (ages ≤50 years-old; n = 80) or older (>50 years-old; n = 295). Compared to tumors from older patients, tumors from younger patients were less likely to be dMMR/MSI-H (12.5% vs. 21.4%, P = .013) and less likely to have a BRAF mutation (1.5% vs. 16.1%, P = .002). BRAF mutation status was highly associated with MMR status; BRAF-mutated tumors were 29.7 times more likely than BRAF-WT tumors to be dMMR/MSI-H (P = < .001, 95% CI 11.3-78.3).ConclusionsTumors of younger patients were less likely than tumors of older patients to have a dMMR/MSI-H or BRAF mutation. Universal MMR/MSI testing in our dataset identified a relatively large population of older patients with sporadic CRC who were eligible for immunotherapy.     

Prognostic evaluation of VEGFA genotypes and haplotypes in a cohort of Brazilian women with non metastatic breast cancer

Vascular Endothelial Growth Factor (VEGF) mediates angiogenesis, which is crucial for tumor development and progression. The present study aimed to evaluate the impact of VEGFA gene polymorphisms rs699947, rs833061, rs1570360, rs2010963 and rs3025039 on breast cancer features and prognosis. A cohort of Brazilian women (N = 1038) with unilateral non-metastatic breast cancer was evaluated. The association between VEGFA polymorphisms and histopathological features or pathological complete response (pCR) to neoadjuvant chemotherapy was evaluated by the Chi-square test, with calculation of the respective odds ratio (OR) and 95% confidence intervals (95% CI). The impact of individual categories on disease-free survival was evaluated using Kaplan-Meier curves and multivariate Cox proportional hazards regression models for calculation of adjusted hazard ratios (HR_adjusted). Variant genotypes of rs699947 (CA + AA) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.82; 95% CI = 1.15 – 2.89), and with shorter disease-free survival among patients treated with neoadjuvant chemotherapy followed by mastectomy (HR_adjusted = 1.82; 95% CI = 1.16 – 2.86). Variant genotypes of rs833061 (TC + CC) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.79; 95% CI = 1.12 – 2.84) and with positive lymph node status (OR = 1.34; 95% CI = 1.01 – 1.77), but showed no independent effect on disease-free survival. Variant haplotypes (*2 to *5) appear to favor pCR (OR = 7.1; 95% CI = 1.7 – 30.1). VEGFA genotyping may add to prognostic evaluation of breast cancer, with rs699947 being the most likely to contribute.     

TP53 mutations are associated with higher rates of pathologic complete response to anthracycline/cyclophosphamide‐based neoadjuvant chemotherapy in operable primary breast cancer

The role of TP53 mutations in predicting response to neoadjuvant chemotherapy in breast cancer remains controversial. The aims of this study were to investigate whether TP53 mutations were associated with response and survival in breast cancer patients who received neoadjuvant chemotherapy. Therefore, we identified TP53 mutations in the core‐needle biopsy tumor samples obtained before the neoadjuvant chemotherapy from 351 operable primary breast cancer patients who either received anthracycline/cyclophosphamide‐based (n = 252) or paclitaxel (n = 99) neoadjuvant chemotherapy. We found that 41.0% (144 of 351) of patients harbored TP53 mutations, and 14.8% of patients achieved a pCR (pathologic complete response) after neoadjuvant chemotherapy. Among patients treated with anthracycline/cyclophosphamide (n = 252), patients with TP53 mutations had a significantly higher pCR rate than those with wild‐type (28.6 vs.7.1%; p < 0.001), and TP53 mutation was an independent favorable predictor of pCR [odds ratio (OR) = 3.41; 95% confidence interval (CI) 1.50–7.77; p = 0.003] in this group; moreover, patients with TP53 mutation had a better distant recurrence‐free survival (DRFS) than those with wild‐type [unadjusted hazard ratio (HR) = 0.43; 95% CI 0.20–0.94; p = 0.030] in this group. Among patients treated with paclitaxel (n = 99), no significant difference in pCR rates was observed between patients with or without TP53 mutations (15.2 vs. 11.3%; p = 0.57). Our results suggested that patients with TP53 mutations are more likely to respond to anthracycline/ cyclophosphamide‐based neoadjuvant chemotherapy and have a favorable survival.