Can the Neutrophil to Lymphocyte Ratio Predict Complete Pathologic Response to Neoadjuvant Breast Cancer Treatment? A Systematic Review and Meta-analysis

The systemic inflammatory response plays a role in tumor progression and development. The neutrophil to lymphocyte ratio (NLR) is a biochemical marker of systemic inflammation and is increasingly gaining appreciation for its prognostic role in predicting breast cancer outcomes. Previous research has demonstrated that patients who achieve a complete pathologic response (pCR) to neoadjuvant breast cancer treatment have a more favorable disease-free survival. This study aimed to assess whether the NLR can predict pCR to neoadjuvant therapy in breast cancer. A meta-analysis of 8 relevant studies was performed. The primary endpoint included pCR. Secondary endpoint included 5-year disease-free survival. Eight studies were included, reporting on 1586 patients. A total of 363 (22.88%) patients achieved pCR post neoadjuvant therapy. A lower NLR was associated with a greater rate of pCR (odds ratio, 1.83; 95% confidence interval, 1.15-2.91; P = .0003). Only 4 studies produced data on disease-free survival. A lower NLR was associated with a higher 5-year disease-free survival; however, this did not achieve statistical significance (hazard ratio, 1.38; 95% confidence interval, 0.82-2.31; P = .02). Sub-group analysis of sample size, NLR value, and geographic location proved statistically significant in determining an association between NLR and pCR. This meta-analysis found NLR to be a predictor for pCR in patients with breast cancer. All of the studies reviewed were retrospective cohort studies. Adequately sized, prospective clinical trials are needed to understand if NLR could become an important prognostic indicator of pCR.     

Can We Predict Response and/or Resistance to Neoadjuvant Chemoradiotherapy in Patients with Rectal Cancer?

The current management of locally advanced rectal cancer consists of neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. Response to CRT varies significantly, and the ability to predict responsiveness, so that treatment modalities can be tailored to the tumor biology of the individual patient, remains a pressing goal. Although many studies have reported promising findings, no markers of response or resistance have been validated and widely incorporated into clinical use. However, many ongoing prospective clinical trials have the potential to dramatically change the standard of care for rectal cancer. This review summarizes the current understanding of predictors of response to CRT, ranging from patient-specific factors to radiologic modalities, with a special emphasis on the rapidly expanding field of molecular biomarkers derived from genomic data.     

“Initial Clinical Response” to Neoadjuvant Chemotherapy: An In-vivo Chemosensitivity Test for Efficacy in Patients with Advanced Breast Cancer

Neoadjuvant chemotherapy (NACT) is well established as the standard of care and initial management ofchoice for patients with advanced breast cancer (ABC). The response is however not uniform. The present studywas an endeavor to develop a clinically applicable tool based on the available clinico-pathological data in theroutine clinical setting to predict response to chemotherapy in breast cancer in a developing country. From 1stJune 2005 to 30th June 2007, 149 patients registered at INMOL hospital with ABC at initial diagnosis havingtumor size 5 cm or more and treated with FAC as NACT were prospectively included in the study to analyzeassociation of response after first cycle of chemotherapy (initial clinical response) with that after the thirdcycle. Tumor measurements were done at base line (before starting chemotherapy), three weeks after the firstcourse of chemotherapy and three weeks after the third course. Percentage change was calculated for the lattertwo stages. Clinical response was assessed according to WHO/UICC criteria. Pathological complete response(pCR) was based on the histopathology of the operative specimen after NACT. 67.1% patients (cCR 7.4%+cPR59.7%) responded to chemotherapy while 32.9% (cSD 23.5%+cPD 9.4%) did not. pCR rate was 4%. No patienthad initial clinical complete response while 23% had icPR, 74% had icSD and 3% had icPD. All patients withicPR responded to NACT (cCR 29%+cPR 71%) while 60% of icSD responded to chemotherapy (cCR 1%+cPR59%) and 40% of icSD failed to respond (cSD 31%+cPD 9%). All patients with icPD developed cPD. The highsensitivity of initial clinical response for prediction of cCR and 100% specificity of icPD for prediction of cPDfavors its incorporation in clinical practice, as an early predictor of response to NACT in ABC patients.     

Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography–Computed Tomography in Monitoring the Response of Breast Cancer to Neoadjuvant Chemotherapy: A Meta–Analysis

IntroductionTo evaluate the diagnostic performance of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in monitoring the response of breast cancers to neoadjuvant chemotherapy.MethodsArticles published in medical and oncologic journals between January 2000 and June 2012 were identified by systematic MEDLINE, Cochrane Database for Systematic Reviews, and EMBASE, and by manual searches of the references listed in original and review articles. Quality of the included studies was assessed by using the quality assessment of diagnosis accuracy studies score tool. Meta-DiSc statistical software was used to calculate the summary sensitivity and specificity, positive predictive and negative predictive values, and the summary receiver operating characteristics curve (SROC).ResultsFifteen studies with 745 patients were included in the study after meeting the inclusion criteria. The pooled sensitivity and specificity of FDG-PET or PET/CT were 80.5% (95% CI, 75.9%-84.5%) and 78.8% (95% CI, 74.1%-83.0%), respectively, and the positive predictive and negative predictive values were 79.8% and 79.5%, respectively. After 1 and 2 courses of chemotherapy, the pooled sensitivity and false-positive rate were 78.2% (95% CI, 73.8%-82.5%) and 11.2%, respectively; and 82.4% (95% CI, 77.4%-86.1%) and 19.3%, respectively.ConclusionsAnalysis of the findings suggests that FDG-PET has moderately high sensitivity and specificity in early detection of responders from nonresponders, and can be applied in the evaluation of breast cancer response to neoadjuvant chemotherapy in patients with breast cancer.     

Circulating Tumor Cells in Metastatic Breast Cancer：Monitoring Response to Chemotherapy and Predicting Progression-Free Survival

Objective  

The purpose of this study is to explore RT-PCR method to set up the examination platform for detecting circulating tumor cells (CTC) in peripheral blood from metastatic breast cancer patients. The primary endpoint is to find out the correlation of existence of CTC with clinical responses and progression-free survival (PFS).     

Neoadjuvant Chemotherapy: Does It Have Benefits for the Surgeon in the Treatment of Advanced Squamous Cell Cancer of the Oral Cavity?

The purpose of this clinicopathological study was to evaluate the effects and efficiency of combined neoadjuvant chemotherapy related to surgical margin. 100 consecutively treated squamous cell cancer patients receiving a combined neoadjuvant therapy were selected (Bleomycin—Vincristin—Methotrexate (BVM) or BVM + Mitolactol or BVM + Cisplatin). After three courses of chemotherapy, the patients were operated on. The largest diameter of the primary tumors was compared before and after chemotherapy. In the surgical specimen, the involvement of surgical margin was assessed. The largest diameter before chemotherapy was: T2 30%; T3 55%; T4A 15%. After chemotherapy, the rest tumor was assessed in the surgical specimen as: no rest 11%; <2 cm 57%; 2–4 cm 28%; 4–6 cm 4%. The no rest and <2 cm (optimal operability) tumor was observed in T2: 94%; in T3: 73%; in the T4A: 0%. Severe side effects (Grade III–IV) were not observed. There was a significant decrease in size (P < 0.0001). Of the 100 surgical specimens, 83% had clear-, 9% close- and 8% involved margins. From T4A, there was a 40% (6 patients) involved margin. Based on the significantly better size and operability of primary T2-3, the mild side effects and the high (83%) percentage of clear surgical margins, that is better than other (without preoperative chemotherapy) results, sought the use of chemotherapy is recommended before surgery. Due to the 40% involved margin, we don’t suggest surgery in T4A.     

Patients with Recurrent Breast Cancer: Does the Primary Axillary Lymph node Status Predict more Aggressive Tumor Progression?

BACKGROUND: The extent of axillary lymph node involvement represents the foremost important prognostic parameter in primary breast cancer, and, thus, is one of the main determinants for subsequent systemic treatment. Nevertheless, the relevance of the initial axillary lymph node status on survival after disease recurrence is discussed controversially. Persisting prognostic impact after relapse would identify lymph node status as a marker for tumor biology, in contrast to a simply time-dependent phenomenon. METHOD: Retrospective analysis of 813 patients with locoregional or distant recurrence of primary breast cancer, who were primarily diagnosed with their disease at the I. Frauenklinik, Ludwig-Maximilians-University, Munich, and the University Hospital in Berlin-Charlottenburg, Germany, between 1963 and 2000. To be eligible, patients were required to have been treated for resectable breast cancer free of distant disease at the time of primary diagnosis, and must have undergone systematic axillary lymph node dissection. Patients with unknown tumor size or nodal status were excluded from the study. All data were gathered contemporaneously and compared with original patients files, as well as the local cancer registry, ensuring high quality of data. The median observation time was 60 (standard deviation 44) months. RESULTS: At time of primary diagnosis, 273 patients (33.6%) were node-negative, while axillary lymph node metastases were detected in 540 patients (66.4%). In univariate analysis tumor size, axillary lymph node status, histopathological grading, hormone receptor status, as well as peritumoral lymphangiosis and haemangiosis carcinomatosa were significantly correlated with survival after relapse (all, P < 0.0001). Kaplan-Meier analysis estimated the median survival time after relapse in node-negative patients to be 42 months (31-52 months, 95% CI), and 20 months in patients with 1-3 axillary lymph node metastases (16-24 months, 95% CI), compared to 13 months in patients with at least 4 involved axillary nodes (12-15 months, 95% CI). Multivariate logistic regression analysis, allowing for tumor size, axillary lymph node status, histopathological grading, presence of lymphangiosis carcinomatosa, relapse site and disease-free interval confirmed all parameters, except of histopathological grading (P = 0.14), as significant, independent risk factors for cancer associated death. Subgroup analyses, accounting for site of relapse and duration of disease-free interval, confirmed primary lymph node status as independent predictor for cancer-associated death after relapse. CONCLUSION: Lymph node involvement at primary diagnosis of breast cancer patients predicts an unfavorable outcome after first recurrence, independently of the site of relapse and disease-free interval. These observations support the hypothesis that primary lymph node involvement is not a merely time-dependent indicator for tumor progression, but indicates tumors with aggressive biological behavior.     

Can Nomograms Predict Non–Sentinel Lymph Node Metastasis After Neoadjuvant Chemotherapy in Sentinel Lymph Node–Positive Breast Cancer Patients?

BackgroundThe predictive probability of breast cancer nomograms for non–sentinel node metastases (NSLNM) after neoadjuvant chemotherapy (NCT) in patients with a positive sentinel lymph node (SLN) biopsy is unknown. The aim of this study was to evaluate the accuracy of 3 different nomograms in patients receiving NCT.Patients and MethodsBetween 1999 and 2007, 54 patients presented with clinically N0 disease received NCT. Nomograms developed by Memorial Sloan-Kettering Cancer Center (MSKCC), Stanford University, and Tenon Hospital were used to calculate the probability of NSLNM by using tumor size at presentation and after NCT for the same patient. The discrimination of the nomograms was assessed by calculating the area under (AUC) the receiver operating characteristic curve, and it was accepted that AUC values 0.7-0.8 represent considerable discrimination.ResultsThe median patient age was 50.9 years (range, 29–67 years). Twenty-two patients (38.8%) had positive NSLNM. The MSKCC and the Stanford nomograms yielded similar AUC regardless of whether initial or post-NCT tumor size was used to determine predicted probability of NSLNM (AUCs were < 0.70). AUC was 0.74 for the Tenon model using tumor size at presentation. After NCT, the AUCs were 0.64, 0.57, and 0.78 for the MSKCC, the Stanford, and the Tenon nomograms, respectively.ConclusionAlthough the AUC of the Tenon model was acceptable for accuracy, we found a lower rate for predicting negative NSLNM in our group than in the Tenon Hospital report. All of the nomograms developed for use in the non-NCT population need to be used with caution in the NCT population     

Is Technetium-99m Sestamibi Imaging Able to Predict Pathologic Nonresponse to Neoadjuvant Chemotherapy in Breast Cancer? A Meta-analysis Evaluating Current Use and Shortcomings

Background

Interest in technetium-99m (^99mTc)-sestamibi imaging for neoadjuvant chemotherapy (NAC) response monitoring in locally advanced breast cancer (LABC) is increasing but remains matter of discussion. The present study conducted a meta-analysis of the diagnostic performance of ^99mTc-sestamibi to predict pathologic nonresponse to NAC for primary LABC.

Functional Imaging to Predict Treatment Response in Head and Neck Cancer: How Close are We to Biologically Adaptive Radiotherapy?

It is increasingly recognised that head and neck cancer represents a spectrum of disease with a differential response to standard treatments. Although prognostic factors are well established, they do not reliably predict response. The ability to predict response early during radiotherapy would allow adaptation of treatment: intensifying treatment for those not responding adequately or de-intensifying remaining therapy for those likely to achieve a complete response. Functional imaging offers such an opportunity. Changes in parameters obtained with functional magnetic resonance imaging or positron emission tomography-computed tomography during treatment have been found to be predictive of disease control in head and neck cancer. Although many questions remain unanswered regarding the optimal implementation of these techniques, current, maturing and future studies may provide the much-needed homogeneous cohorts with larger sample sizes and external validation of parameters. With a stepwise and collaborative approach, we may be able to develop imaging biomarkers that allow us to deliver personalised, biologically adaptive radiotherapy for head and neck cancer.     

Can CD44+/CD24- Tumor Cells Be Used to Determine the Extent of Breast Cancer Invasion Following Neoadjuvant Chemotherapy?

Purpose

To investigate the distribution of CD44⁺/CD24^- cells in breast cancers in relation to tumor size before and after the administration of neoadjuvant chemotherapy.

Methods

CD44⁺/CD24^- tumor cells obtained from breast cancer specimens were characterized in vivo and in vitro using tumor formation assays and mammosphere generation assays, respectively. The distribution of CD44+/CD24- tumor cells in 78 breast cancer specimens following administration of neoadjuvant chemotherapy was also evaluated using immunofluorescence assays, and this distribution was compared with the extent of tumor invasion predicted by Response Evaluation Criteria in Solid Tumours (RECIST).

Results

In 27/78 cases, complete remission (CR) was identified using RECIST. However, 18 of these CR cases were associated with a scattered distribution of tumor stem cells in the outline of the original tumor prior to neoadjuvant chemotherapy. After neoadjuvant chemotherapy, 24 cases involved cancer cells that were confined to the tumor outline, and 21 cases had tumor cells or tumor stem cells overlapping the tumor outline. In addition, there were 6 patients who were insensitive to chemotherapy, and in these cases, both cancer cells and stem cells were detected outside the contours of the tumor volume imaged prior to chemotherapy.

Conclusion

CD44+/CD24- tumor cells may be an additional parameter to evaluate when determining the extent of breast cancer invasion.     

Prolonged Survival of Patients With Non–Small-Cell Lung Cancer With Leptomeningeal Carcinomatosis in the Modern Treatment Era

IntroductionLeptomeningeal carcinomatosis (LM) is a severe complication of non–small-cell lung cancer (NSCLC) historically associated with poor prognosis. New chemotherapeutic and targeted treatments could potentially affect the natural history of LM.Patients and MethodsPatients with a pathologic diagnosis of NSCLC with LM treated at Stanford between 2003 and 2011 were identified via institutional databases and medical records. LM was defined by cerebrospinal fluid (CSF) that was positive for malignant cells or by LM enhancement on magnetic resonance imaging with gadolinium contrast. Retrospective, landmark analyses were performed to estimate survival. Statistical analyses were performed using SAS Enterprise Guide, version 4.3.ResultsLM was identified in 30 patients. All cases were adenocarcinoma; 60% of patients had a known or suspected driver mutation. The mean age was 58 years. Of the 30 patients, 67% were women; 70% were nonsmokers; 27% initially presented with LM; 84% received systemic treatment at or after development of LM; and 53% of these patients received modern systemic therapy for their LM, defined as a regimen containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor. Mean overall survival after LM diagnosis was 6 months (95% CI, 3-12). Patients who received modern systemic therapy for LM had decreased hazard of death (hazard ratio [HR], 0.24; P = .007).ConclusionIn this retrospective, single-institution analysis, median survival with LM was higher compared with historical experience. Patients who received modern systemic therapy for their LM had particularly good outcomes. These data provide evidence for improving survival outcomes in the modern treatment era for this difficult-to-treat complication.     

Clinicopathologic Factors Associated With Response to Neoadjuvant Anti-HER2–Directed Chemotherapy in HER2-Positive Breast Cancer

BackgroundHER2-targeted neoadjuvant therapy has high efficacy in treating HER2-positive breast cancer. Response to neoadjuvant therapy helps clinicians make treatment decisions and make estimates about prognosis. This study examined clinicopathologic features to determine which may be most predictive of response to neoadjuvant therapy in HER2⁺ breast cancer.Patients and MethodsPatients with HER2⁺ breast cancer (n = 173) who had an initial biopsy performed between 2010 and 2016 were identified at our institution. Tumor response was evaluated on excisional specimens using the MD Anderson residual cancer burden (RCB) classification. Tumors with pathologic complete response (defined as no residual invasive carcinoma in the breast and lymph nodes) and RCB-I were classified as having response and tumors with RCB-II and -III as having no response. Patient age, tumor size, nuclear grade (1/2 vs. 3), mitosis, Nottingham grade, HER2 immunohistochemistry (1/2+ vs. 3+), HER2/CEP17 (chromosome enumeration probe 17) ratio, HER2 copy number, estrogen receptor, progesterone receptor, Ki-67, and tumor-infiltrating lymphocytes (TIL) were evaluated and correlated with response. TILs were evaluated for an average and also for the hot spot/total tumor stromal ratio.ResultsSmall tumor size, low estrogen receptor and progesterone receptor expression, HER2 immunohistochemistry 3+, high Ki-67, high HER2/CEP17 ratio, and high HER2 copy number were significantly associated with response (all P < .05). TIL hot spot was associated with RCB in univariate (P < .05) but not multivariate analyses.ConclusionClinicopathologic features may help predict HER2⁺ breast cancer response to neoadjuvant therapy. Larger studies would be useful to confirm these associations, which may have relevance to clinical practice.     

Response and Prognosis of Docetaxel and Cyclophosphamide as Neoadjuvant Chemotherapy in ER+ HER2− Breast Cancer: A Prospective Phase II Study

BackgroundAlthough a docetaxel and cyclophosphomide (TC) regimen without anthracycline as adjuvant therapy became one of the standard regimens especially for ER-positive (ER⁺)/human epidermal growth factor receptor 2-negative (HER2⁻) primary breast cancer, the efficacy of TC as neoadjuvant chemotherapy (NAC) is not known. We conducted the prospective trial to assess the efficacy of a TC regimen in the neoadjuvant setting for stage II to III ER⁺/HER2⁻ primary breast cancer.Patients and MethodsA TC regimen that included 75 mg/m² of docetaxel and 600 mg/m² of cyclophosphamide for 4 cycles every 3 weeks was administered as NAC. Primary endpoints are the rate of clinical response (clinical partial response and clinical complete response) and pathologic complete response; secondary endpoints are the disease-free survival and overall survival rates.ResultsThirty (71.4%) of 42 tumors had clinical response. No patient achieved pathologic complete response. At the median follow-up period of 105.2 months (range, 12.1-119.7 months), the disease-free survival rate was 81.6%, and the distant disease-free survival rate was 86.8%. In terms of survival, only 1 patient died during the study period. The overall survival rate was 97.4% during the study period. Patients who developed distant recurrence had a trend to have progesterone receptor-negative or weakly positive compared with those who did not develop any recurrence (85.7% vs. 45.2%; P = .05).ConclusionsOur prospective study showed that a TC regimen as NAC achieved a high clinical response rate in stage II to III ER⁺/HER2⁻ breast cancer. A TC regimen without anthracycline as NAC might be one of the options for patients with ER⁺/HER2⁻ breast cancer without high-risk factors including progesterone receptor negativity.     

Does Celecoxib Have a Role in the Treatment of Patients with Colorectal Cancer?

The outcome of advanced colorectal cancer (CRC) has steadily improved with the addition of several novel agents. However, chemotherapy is associated with significant toxicities such as diarrhea and bone marrow suppression. Celecoxib has been associated with decreased gastrointestinal toxicity and improved chemotherapy tolerance in preclinical in vivo models, resulting in its investigation in CRC clinical trials. These trials failed to show any improvements in efficacy or reduction in chemotherapy-induced toxicity. This article summarizes relevant preclinical and clinical investigations of celecoxib in CRC.