Biomarkers that Predict Response to Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer

Neoadjuvant chemoradiation has been a standard of care for locally advanced rectal cancers. Recent reports suggest that a pathologic complete response to neoadjuvant treatment correlates to improved overall survival. In addition, some series suggest that patients who have a complete response to neoadjuvant therapy may safely defer surgery in favor of a “watch and wait” approach, therefore avoiding the potential complications and adverse bowel function associated with surgery. It is therefore important to understand the clinical and biologic factors which affect the response of rectal cancers to chemoradiation. This review highlights the current literature examining the biomarkers of tumor response to chemoradiation.     

SUVmax、Ki-67、p53、EGFR对三阴性乳腺癌新辅助化疗疗效的预测价值

目的 探讨18F-FDG PET/CT化疗前SUVmax、Ki-67、p53、EGFR对三阴性乳腺癌（TNBC）及非三阴性乳腺癌（非TNBC）对新辅助化疗完全病理缓解（pathologic complete response, pCR）率的预测价值。方法 初治TNBC患者27例,非TNBC患者184例,在新辅助化疗前行18F-FDG PET/CT显像并测量其SUVmax,取化疗前乳腺肿瘤组织进行Ki-67、p53、EGFR免疫组织化学分析并计算化疗后完全pCR率。结果 TNBC新辅助化疗前的SUVmax明显高于非TNBC的SUVmax（P=0.045）,TNBC新辅助化疗后pCR率明显高于非TNBC（P＜0.001）。在TNBC以及非TNBC中,达到pCR组的化疗前SUVmax与未达到pCR组之间差异无统计学意义（P＞0.05）。Ki-67、p53、EGFR阳性表达组的pCR率与阴性表达组之间差异无统计学意义（P＞0.05）。结论 TNBC对新辅助化疗的敏感度高于非TNBC,且TNBC化疗前SUVmax高于非TNBC,提示TNBC具有较高的能量代谢。化疗前SUVmax以及Ki-67、p53、EGFR不能预测TNBC及非TNBC新辅助化疗的pCR。     

Survivin、p53、Ki-67在乳腺癌组织中的表达及其意义

目的 检测乳腺癌及癌旁组织中Survivin、p53、Ki-67蛋白的表达,探讨它们的相关性及临床意义。方法 采用免疫组化SP法检测60例乳腺癌组织,60例癌旁乳腺正常组织中Survivin、p53、Ki-67的表达。结果 60例乳腺癌组织中Survivin蛋白的阳性表达率为78.33%,明显高于癌旁正常组织5.00%（P〈0.05）,但与乳腺癌的病理分级和淋巴结转移状况无显著相关。p53和Ki-67在乳腺癌组织中表达高于癌旁组织,并与乳腺癌病理分级、腋窝淋巴结转移有关。乳腺癌组织中Survivin的表达与p53和Ki-67表达呈正相关。结论 Survivin、p53、Ki-67蛋白可通过抑制细胞凋亡,对乳腺癌发生和发展起重要作用,p53和Ki-67可以作为乳腺癌的预后指标。在乳腺癌发展中起协同作用。     

Current Views on the Interval Between Neoadjuvant Chemoradiation and Surgery for Rectal Cancer

Neoadjuvant chemoradiation (CRT) has been established as standard treatment for stage II and III rectal cancer, and delayed interval between CRT and rectal resection has emerged as appropriate treatment due to the marked benefits associated with this approach. Despite favorable findings on downstaging and pathological complete response without increasing in morbidity and mortality, no significant improvement in sphincter preservation rate and rectal cancer overall survival has been observed with the current recommended 6–8-week interval. Trials are currently underway and may provide answers regarding the optimal interval between CRT and surgical resection, but until now, the best interval between CRT and surgery remains unclear.     

分子预测直肠癌新辅助放化疗后pCR的研究进展

摘 要：局部晚期直肠癌（LARC）目前的基本治疗策略是新辅助放化疗（nCRT）和随后的全直肠系膜切除术（TME）。nCRT 后的肿瘤消退在个体间差异显著,病理完全缓解（pCR）是 LARC 的预后因素。明确放化疗反应的预测因素有助于临床医生鉴别可能从多模式治疗中获益的患者,并在早期对其预后进行评估。本文结合近年的相关研究,探讨LARC在新辅助治疗后可能达到pCR的分子预测因子。     

Survival After Induction Chemotherapy and Chemoradiation Versus Chemoradiation and Adjuvant Chemotherapy for Locally Advanced Rectal Cancer

BackgroundTotal neoadjuvant therapy (TNT) improves tumor response in locally advanced rectal cancer (LARC) patients compared to neoadjuvant chemoradiotherapy alone. The effect of TNT on patient survival has not been fully investigated.Materials and MethodsThis was a retrospective case series of patients with LARC at a comprehensive cancer center. Three hundred and eleven patients received chemoradiotherapy (chemoRT) as the sole neoadjuvant treatment and planned adjuvant chemotherapy, and 313 received TNT (induction fluorouracil and oxaliplatin-based chemotherapy followed by chemoradiotherapy in the neoadjuvant setting). These patients then underwent total mesorectal excision or were entered in a watch-and-wait protocol. The proportion of patients with complete response (CR) after neoadjuvant therapy (defined as pathological CR or clinical CR sustained for 2 years) was compared by the χ² test. Disease-free survival (DFS), local recurrence-free survival, distant metastasis-free survival, and overall survival were assessed by Kaplan-Meier analysis and log-rank test. Cox regression models were used to further evaluate DFS.ResultsThe rate of CR was 20% for chemoRT and 27% for TNT (P=.05). DFS, local recurrence-free survival, metastasis-free survival, and overall survival were no different. Disease-free survival was not associated with the type of neoadjuvant treatment (hazard ratio [HR] 1.3; 95% confidence interval [CI] 0.93-1.80; P = .12).ConclusionsAlthough TNT does not prolong survival than neoadjuvant chemoradiotherapy plus intended postoperative chemotherapy, the higher response rate associated with TNT may create opportunities to preserve the rectum in more patients with LARC.     

Predictive Significance of p53, Ki-67, and Bcl-2 Expression for Pathologic Complete Response after Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer

Purpose

Patients with triple-negative breast cancer (TNBC) with pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) have superior survival outcomes compared to those with residual disease after NAC. This study investigated the value of three biomarkers, p53, Ki-67, and Bcl-2 for predicting pCR in NAC-treated patients with TNBC.

Methods

Between 2003 and 2012, 198 patients with pathologically confirmed primary TNBC were treated with two different taxane-based chemotherapeutic regimens prior to surgery. Before NAC, expression of p53 (cutoff 25%), Ki-67 (cutoff 10%), and Bcl-2 (cutoff 10%) was assessed immunohistochemically in core biopsy specimens. The incidence of pCR was correlated with the expression of these biomarkers.

Results

Overall, pCR occurred in 37 of the 198 patients (18.7%). A significant association was observed between the pCR rate and overexpression of the p53 and Ki-67 biomarkers. Multivariate analysis showed that only p53 expression was independently associated with pCR to NAC (odds ratio, 3.961; p=0.003). The sensitivity, specificity, positive predictive value, and negative predictive value of p53 expression for predicting pCR were 77.8%, 50.3%, 26.2%, and 90.9%, respectively. The pCR rate was the lowest (5.2%) in patients with low expression of both p53 and Ki-67, and it was the highest (25.8%) when both biomarkers showed high expression.

Conclusion

Expression of p53 was significantly associated with pCR after NAC in patients with TNBC, suggesting that this biomarker might be particularly valuable in identifying TNBC patients prone to have residual disease after NAC.     

Expression of Ki-67, p53 and VEGF in Pediatric Neuroblastoma

Background: Neuroblastoma (NB), is a neuroectodermal tumor derived from neural crest cells, and it is thesecond most common pediatric malignant tumor. The biological and clinical behavior of NB is very heterogeneous.This study was conducted to evaluate the expression of Ki-67, p53 and VEGF markers in tissues obtained fromNB patients with different histologic types and stage. Materials and Methods: Tissue microarray (TMA) blockswere constructed from paraffin blocks of the NB tissues. Immunohistochemical staining was performed on TMAsections to detect the expression of Ki-67, p53 and VEGF markers. The association between the expression ofthese markers and clinicopathological parameters were then analyzed. Results: We had 18 patients with NB,one patient with ganglioneuroblastoma (GNB) and one with ganglioneuroma. Ki-67 was expressed in 13 (65%)tumors, and negatively correlated with age, prognosis, histologic type and stage of NB (all p<0.05). High andmoderate expression of VEGF was found in 5% (1/20) and 65% (13/20) of the tumors, respectively; and it waspositively correlated with age, prognosis and histologic types (all p<0.05) and negatively correlated with MKI(mitosis-karyorrhexis index). p53 expression was observed in 10% (2/20) of the tumors, which showed a relativecorrelation with MKI (p value=0.07). Conclusions: VEGF as a candidate for anti-angiogenic targeted therapywas correlated with the development and progression of NB; therefore, VEGF along with Ki-67 can serve as avaluable marker for the prognosis of this tumor type.     

Dosimetric Parameters Predicting Late Small Bowel Toxicity in Patients With Rectal Cancer Receiving Neoadjuvant Chemoradiation

PurposeThe aim of this study was to identify dosimetric parameters that predict late small bowel (SB) toxicity after neoadjuvant long course chemoradiation (CRT) for rectal cancer.Methods and MaterialsFour hundred eighty-six consecutive patients with locally advanced rectal cancers (clinical T3/T4 or N1/N2) who received CRT followed by surgery and had dosimetric data available for analysis were included in this study. The dose-volume relationship between small bowel irradiation and late small bowel toxicity was evaluated and a mathematical model to predict for late SB toxicity was derived.ResultsAmong the 486 patients with a median follow-up of 60 months from completion of radiation, 36 (7.4%) patients experienced ≥ grade 2 and 21 (4.3%) developed ≥ grade 3 late SB toxicity. A statistically significant association between the development of grade ≥3 late small bowel toxicity and the volume of small bowel irradiated was found at each dose level from 5 to 40 Gy (P < .001 for all dose volumes) in 5 Gy intervals. The average SB volume for patients who experienced grade ≥2 SB toxicity was 2149.9 cm³ and the average SB volume for patients who experienced grade ≥3 SB toxicity was 2179.9 cm³. The predicted V30 for a 5% risk for grade ≥2 SB toxicity was 101.5 cm³ and for grade ≥3 SB toxicity was 201.5 cm³. The volume of small bowel receiving at least 30 Gy (V30) was most strongly associated with grade ≥3 SB toxicity.ConclusionsThis study demonstrates the significant dose-volume relationship between volume of small bowel receiving 30 Gy (V30 Gy) and late grade ≥3 SB toxicity. When planning CRT for patients with rectal cancer, restricting V30 to <200 cm³ will be a useful guideline to minimize the 5 year grade ≥3 late SB toxicity to <5%.     

Current Trends in the Rate of Rectal Cancer Restorative Operations in the Era of Neoadjuvant Chemoradiation

Purpose of Review

The following review addresses the relationship between neoadjuvant chemoradiotherapy and the rate of restorative operations in patients with rectal cancer.

Recent Findings

The rate of restorative operations performed for rectal cancer has improved over the past several decades. The relationship between this increase and the addition of neoadjuvant chemoradiotherapy to the treatment regimen for locally advanced rectal cancer is still being defined. Improved rates of sphincter-sparing procedures between patients who receive preoperative chemoradiation compared to those who receive treatment postoperatively have not been supported in the literature. The patients who seem to benefit from neoadjuvant therapy in terms of sphincter preservation are those with distal tumors. Better tumor response to neoadjuvant chemotherapy and longer interval to surgical intervention appear to have little if any benefit to preserving the sphincter.

Summary

Increased rates of restorative operations for rectal cancer seem to be most significant among distal tumors. The reasons for the increase are likely multifactorial and include improvements in patient selection, surgical technique, imaging modalities, and patient care. The role of neoadjuvant chemoradiotherapy in this setting remains equivocal.

     

Current Status of the Watch-and-Wait Policy for Patients with Complete Clinical Response Following Neoadjuvant Chemoradiation in Rectal Cancer

Preoperative chemoradiation is the standard of care for patients with locally advanced rectal cancer to reduce the risk of local recurrence. Chemoradiation can achieve a pathological complete response (pCR) in 10–20% of patients when surgery is performed at 4–12 weeks following completion, and a clinical complete response (cCR) in 15–30% if surgery is withheld. The probability of pCR and cCR is partly dependent on initial clinical T- and N-stage. Observational/retrospective studies suggest a selective watch-and-wait policy with rigorous surveillance, avoiding radical surgery, is a safe option to offer patients who achieve a cCR or near cCR. With a watch-and-wait approach, approximately one third will relapse within 12 months, but regrowth is almost invariably endoluminal, and can often be salvaged without compromising overall survival. The aim of this overview is to examine the current status of the watch-and-wait policy for patients with cCR following chemoradiation in rectal cancer.