ABSTRACT
PURPOSE: Triple-negative breast cancer (TNBC) is a heterogeneous disease with a significant challenge to effectively manage in the clinic worldwide. Immunotherapy may be beneficial to TNBC patients if responders can be effectively identified. Here we sought to elucidate the immune landscape of TNBCs by stratifying patients into immune-specific subtypes (immunotypes) to decipher the molecular and cellular presentations and signaling events of this heterogeneous disease and associating them with their clinical outcomes and potential treatment options. EXPERIMENTAL DESIGN: We profiled 730 immune genes in 88 retrospective Indian TNBC samples using the NanoString platform, established immunotypes using non-negative matrix factorization-based machine learning approach, and validated them using Western TNBCs (n=422; public datasets). Immunotype-specific gene signatures were associated with clinicopathological features, immune cell types, biological pathways, acute/chronic inflammatory responses, and immunogenic cell death processes. Responses to different immunotherapies associated with TNBC immunotypes were assessed using cross-cancer comparison to melanoma (n=504). Tumor-infiltrating lymphocytes (TILs) and pan-macrophage spatial marker expression were evaluated. RESULTS: We identified three robust transcriptome-based immunotypes in both Indian and Western TNBCs in similar proportions. Immunotype-1 tumors, mainly representing well-known claudin-low and immunomodulatory subgroups, harbored dense TIL infiltrates and T-helper-1 (Th1) response profiles associated with smaller tumors, pre-menopausal status, and a better prognosis. They displayed a cascade of events, including acute inflammation, damage-associated molecular patterns, T-cell receptor-related and chemokine-specific signaling, antigen presentation, and viral-mimicry pathways. On the other hand, immunotype-2 was enriched for Th2/Th17 responses, CD4+ regulatory cells, basal-like/mesenchymal immunotypes, and an intermediate prognosis. In contrast to the two T-cell enriched immunotypes, immunotype-3 patients expressed innate immune genes/proteins, including those representing myeloid infiltrations (validated by spatial immunohistochemistry), and had poor survival. Remarkably, a cross-cancer comparison analysis revealed the association of immunotype-1 with responses to anti-PD-L1 and MAGEA3 immunotherapies. CONCLUSION: Overall, the TNBC immunotypes identified in TNBCs reveal different prognoses, immune infiltrations, signaling, acute/chronic inflammation leading to immunogenic cell death of cancer cells, and potentially distinct responses to immunotherapies. The overlap in immune characteristics in Indian and Western TNBCs suggests similar efficiency of immunotherapy in both populations if strategies to select patients according to immunotypes can be further optimized and implemented.
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BACKGROUND: Cancer-related fatigue is widely prevalent in cancer patients and affects quality of life in advanced cancer patients. Fatigue is caused due to both psychologic distress and physiological sequel following cancer progression and its treatment. In this study, we evaluate the effects of yogic intervention in managing fatigue in metastatic breast cancer patients. METHODS: Ninety-one patients with metastatic breast cancer were randomized to receive integrated yoga program (n = 46) or supportive therapy and education (n = 45) over a 3-month period. Assessments such as perceived stress, fatigue symptom inventory, diurnal salivary cortisol, and natural killer cell counts were carried out before and after intervention. Analysis was done using an intention-to-treat approach. Postmeasures for the above outcomes were assessed using ANCOVA with respective baseline measure as a covariate. RESULTS: The results suggest that yoga reduces perceived stress (P = 0.001), fatigue frequency (P < 0.001), fatigue severity (P < 0.001), interference (P < 0.001), and diurnal variation (P < 0.001) when compared to supportive therapy. There was a positive correlation of change in fatigue severity with 9 a.m. salivary cortisol levels. CONCLUSION: The results suggest that yoga reduces fatigue in advanced breast cancer patients.
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BACKGROUND: Studies have shown that distress and accompanying neuroendocrine stress responses as important predictor of survival in advanced breast cancer patients. Some psychotherapeutic intervention studies have shown have modulation of neuroendocrine-immune responses in advanced breast cancer patients. In this study, we evaluate the effects of yoga on perceived stress, sleep, diurnal cortisol, and natural killer (NK) cell counts in patients with metastatic cancer. METHODS: In this study, 91 patients with metastatic breast cancer who satisfied selection criteria and consented to participate were recruited and randomized to receive "integrated yoga based stress reduction program" (n = 45) or standard "education and supportive therapy sessions" (n = 46) over a 3 month period. Psychometric assessments for sleep quality were done before and after intervention. Blood draws for NK cell counts were collected before and after the intervention. Saliva samples were collected for three consecutive days before and after intervention. Data were analyzed using the analysis of covariance on postmeasures using respective baseline measure as a covariate. RESULTS: There was a significant decrease in scales of symptom distress (P < 0.001), sleep parameters (P = 0.02), and improvement in quality of sleep (P = 0.001) and Insomnia Rating Scale sleep score (P = 0.001) following intervention. There was a decrease in morning waking cortisol in yoga group (P = 0.003) alone following intervention. There was a significant improvement in NK cell percent (P = 0.03) following intervention in yoga group compared to control group. CONCLUSION: The results suggest modulation of neuroendocrine responses and improvement in sleep in patients with advanced breast cancer following yoga intervention.
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AIMS: The aim of this study is to compare the effects of yoga program with supportive therapy counseling on mood states, treatment-related symptoms, toxicity, and quality of life in Stage II and III breast cancer patients on conventional treatment. METHODS: Ninety-eight Stage II and III breast cancer patients underwent surgery followed by adjuvant radiotherapy (RT) or chemotherapy (CT) or both at a cancer center were randomly assigned to receive yoga (n = 45) and supportive therapy counseling (n = 53) over a 24-week period. Intervention consisted of 60-min yoga sessions, daily while the control group was imparted supportive therapy during their hospital visits. Assessments included state-trait anxiety inventory, Beck's depression inventory, symptom checklist, common toxicity criteria, and functional living index-cancer. Assessments were done at baseline, after surgery, before, during, and after RT and six cycles of CT. RESULTS: Both groups had similar baseline scores. There were 29 dropouts 12 (yoga) and 17 (controls) following surgery. Sixty-nine participants contributed data to the current analysis (33 in yoga, and 36 in controls). An ANCOVA, adjusting for baseline differences, showed a significant decrease for the yoga intervention as compared to the control group during RT (first result) and CT (second result), in (i) anxiety state by 4.72 and 7.7 points, (ii) depression by 5.74 and 7.25 points, (iii) treatment-related symptoms by 2.34 and 2.97 points, (iv) severity of symptoms by 6.43 and 8.83 points, (v) distress by 7.19 and 13.11 points, and (vi) and improved overall quality of life by 23.9 and 31.2 points as compared to controls. Toxicity was significantly less in the yoga group (P = 0.01) during CT. CONCLUSION: The results suggest a possible use for yoga as a psychotherapeutic intervention in breast cancer patients undergoing conventional treatment.
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AIM: To compare the effects of yoga program with supportive therapy on self-reported symptoms of depression in breast cancer patients undergoing conventional treatment. PATIENTS AND METHODS: Ninety-eight breast cancer patients with stage II and III disease from a cancer center were randomly assigned to receive yoga (n = 45) and supportive therapy (n = 53) over a 24-week period during which they underwent surgery followed by adjuvant radiotherapy (RT) or chemotherapy (CT) or both. The study stoppage criteria was progressive disease rendering the patient bedridden or any physical musculoskeletal injury resulting from intervention or less than 60% attendance to yoga intervention. Subjects underwent yoga intervention for 60 min daily with control group undergoing supportive therapy during their hospital visits. Beck's Depression Inventory (BDI) and symptom checklist were assessed at baseline, after surgery, before, during, and after RT and six cycles of CT. We used analysis of covariance (intent-to-treat) to study the effects of intervention on depression scores and Pearson correlation analyses to evaluate the bivariate relationships. RESULTS: A total of 69 participants contributed data to the current analysis (yoga, n = 33, and controls, n = 36). There was 29% attrition in this study. The results suggest an overall decrease in self-reported depression with time in both the groups. There was a significant decrease in depression scores in the yoga group as compared to controls following surgery, RT, and CT (P < 0.01). There was a positive correlation (P < 0.001) between depression scores with symptom severity and distress during surgery, RT, and CT. CONCLUSION: The results suggest possible antidepressant effects with yoga intervention in breast cancer patients undergoing conventional treatment.
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BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of nimotuzumab in combination with chemotherapy (docetaxel and carboplatin) versus chemotherapy alone in patients with stage IIIB/IV non-small-cell lung cancer. METHODS: This multicenter, open-label, Phase II study randomized 110 patients to receive nimotuzumab plus chemotherapy (nimotuzumab group) or chemotherapy alone (control group), and comprised concomitant, maintenance, and follow-up phases. Nimotuzumab 200 mg was administered once weekly for 13 weeks during the first two phases with four cycles of chemotherapy and docetaxel 75 mg/m(2) and carboplatin (area under the curve 5 mg/mL*min) every 3 weeks for a maximum of four cycles during the concomitant phase. The primary endpoint was objective response rate (sum of complete response and partial response). Secondary endpoints, ie, overall survival and progression-free survival, were estimated using the Kaplan-Meier method. Efficacy was evaluated on the intent-to-treat and efficacy-evaluable sets. Safety was assessed from adverse event and serious adverse event data. RESULTS: The objective response rate was significantly higher in the nimotuzumab group than in the control group in the intent-to-treat population (54% versus 34.5%; P=0.04). A complete response and partial response were achieved in 3.6% and 50% of patients, respectively, in the nimotuzumab group, and in 4% and 30.9% of patients, respectively, in the control group. No significant differences in median progression-free survival and overall survival were observed. Safety profiles were comparable between the two groups. CONCLUSION: Nimotuzumab plus chemotherapy significantly improved the objective response rate as compared with chemotherapy alone. The combination was safe and well tolerated in patients with stage IIIB/IV non-small-cell lung cancer.
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OBJECTIVES: This study compares the anxiolytic effects of a yoga program and supportive therapy in breast cancer outpatients undergoing conventional treatment at a cancer centre. METHODS: Ninety-eight stage II and III breast cancer outpatients were randomly assigned to receive yoga (n=45) or brief supportive therapy (n=53) prior to their primary treatment i.e., surgery. Only those subjects who received surgery followed by adjuvant radiotherapy and six cycles of chemotherapy were chosen for analysis following intervention (yoga, n=18, control, n=20). Intervention consisted of yoga sessions lasting 60min daily while the control group was imparted supportive therapy during their hospital visits as a part of routine care. Assessments included Speilberger's State Trait Anxiety Inventory and symptom checklist. Assessments were done at baseline, after surgery, before, during, and after radiotherapy and chemotherapy. RESULTS: A GLM-repeated measures ANOVA showed overall decrease in both self-reported state anxiety (p<0.001) and trait anxiety (p=0.005) in yoga group as compared to controls. There was a positive correlation between anxiety states and traits with symptom severity and distress during conventional treatment intervals. CONCLUSION: The results suggest that yoga can be used for managing treatment-related symptoms and anxiety in breast cancer outpatients.
