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Small-cell lung cancer (SCLC) remains a disease with poor prognosis, particularly in extensive-stage SCLC (ES-SCLC). Current standard-of-care treatment includes chemotherapy with platinum agents and etoposide plus immunotherapy with atezolizumab or durvalumab, which has achieved a mean overall survival of 12-13 months in clinical trials. However, long-term survival in ES-SCLC, even with the addition of immunotherapy, continues to be rare. We present the case of a middle-aged male patient diagnosed with ES-SCLC who was treated with four cycles of induction chemotherapy (carboplatin and etoposide) and atezolizumab, starting maintenance atezolizumab every 21 days thereafter, and thoracic radiotherapy. After 9 months, he experienced mild disease progression and was rechallenged with six cycles of carboplatin and etoposide with continued atezolizumab. Subsequent imaging showed near-complete disease resolution which has been sustained since. He has continued on maintenance atezolizumab since diagnosis and has achieved 60 months overall survival and 44 months progression-free survival. Throughout treatment, he has maintained a high functional capacity and only experienced one immune-related adverse event. Our patient is representative of a small subset who are capable of achieving durable responses to immunotherapy and his case highlights the need for further research to elucidate the clinical and biological factors driving this response.
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Anticuerpos Monoclonales Humanizados , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Masculino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del Tratamiento , Etopósido/uso terapéuticoRESUMEN
Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space.
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BACKGROUND: Immune checkpoint inhibitor (ICI) therapy for patients undergoing cancer treatment carries a risk of severe immune-related adverse events (IRAEs). Questions remain about whether seasonal influenza vaccination might increase the risk of developing IRAEs among these patients given that vaccines are immunomodulatory. Previous vaccine safety studies on patients with cancer prescribed ICI therapy have demonstrated conflicting results. METHODS: Using health administrative data from Ontario, Canada among adults diagnosed with cancer who had been prescribed ICI therapy and who had received an influenza vaccine from 2012 to 2019, we conducted a self-controlled case series study. The pre-vaccination control period started 42-days post-ICI initiation until 14-days prior to vaccination, the risk period was 1-42 days post-vaccination, and the post-vaccination control period was after the risk period until ICI discontinuation or a maximum period of two years. Emergency department (ED) visit(s) and/or hospitalization for any cause after ICI initiation was used to identify severe IRAEs. We fitted a fixed-effects Poisson regression model accounting for seasonality and calendar time to estimate relative incidence of IRAEs between risk and control periods. RESULTS: We identified 1133 records of cancer patients who received influenza vaccination while prescribed ICI therapy. Most were aged ≥ 66 years (73 %), were male (63 %), had lung cancer (54 %), and had received ICI therapy with a programmed cell death protein 1(PD-1) inhibitor (91 %). A quarter (26 %) experienced an ED visit and/or hospitalization during the observation period. Rates of ED visits and/or hospitalizations in the risk vs. control periods were similar, with an incidence rate ratio of 1.04 (95 % CI: 0.75-1.45). Subgroup and sensitivity analyses yielded similar results. CONCLUSION: Seasonal influenza vaccination was not associated with an increased incidence of ED visit or hospitalization among adults with cancer treated with ICI therapy and our results support further evidence of vaccine safety.
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Vacunas contra la Influenza , Gripe Humana , Neoplasias Pulmonares , Neoplasias , Adulto , Humanos , Masculino , Femenino , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Gripe Humana/prevención & control , Gripe Humana/etiología , Estaciones del Año , Proyectos de Investigación , Vacunación/efectos adversos , Ontario/epidemiología , Estudios RetrospectivosRESUMEN
PURPOSE: In the past decade, immune checkpoint inhibitors (ICIs) have emerged as a treatment option for metastatic breast cancer (BC). More recently, ICIs have been approved in the perioperative setting. This has led to clinical scenarios where radiation therapy (RT) is given concurrently with ICIs. On the other hand, moderate and ultrahypofractionated schedules of RT are being widely adopted in the adjuvant setting, in addition to an increased use of metastasis-directed therapy. Furthermore, RT can modulate the tumor microenvironment and induce a systemic response at nonirradiated sites, an "abscopal effect." The amplification of antitumor immune response is used as the rationale behind the concomitant use of ICIs and RT. To date, there is a lack of literature on the optimal sequence, timing, dose/fractionation schema, and treated RT volumes with ICIs in patients with BC, especially in the era of ultrahypofractionation. METHODS AND MATERIALS: We conducted a systematic review to delineate the reported treatment details, safety, and efficacy of combining ICI and RT in patients with BC. PubMed, Embase, and Cochrane CENTRAL were searched between 2014 and 2023. Data were extracted to assess the details of ICIs/RT delivery, safety, and efficacy. RESULTS: Of the 12 eligible studies, 9 involved patients with metastatic BC. Most studies were phase 1/2, had a small sample size (range, 8-28), and were heterogenous in patient population and reported outcomes. The combination was reported to be safe. We identified 1 study in the perioperative setting, which did a posthoc analysis of safety/efficacy of ICIs in the adjuvant setting with receipt and pattern of RT. CONCLUSIONS: In conclusion, there are limited data on the dose, timing, fractionation, and volumes of RT in both the adjuvant and metastatic setting in BC. Ongoing/future trials should collect and report such data on RT details, whenever RT is used in combination with ICIs.
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Neoplasias de la Mama , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Humanos , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/patología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Terapia Combinada/métodos , Fraccionamiento de la Dosis de RadiaciónRESUMEN
BACKGROUND: The overexpression of the human epidermal growth factor receptor 2 (HER2+) accounts for 15-20% of all breast cancer phenotypes. Even after the completion of the standard combination of chemotherapy and trastuzumab, relapse events occur in approximately 15% of cases. The neoadjuvant approach has multiple benefits that include the potential to downgrade staging and convert previously unresectable tumors to operable tumors. In addition, achieving a pathologic complete response (pCR) following preoperative systemic treatment is prognostic of enhanced survival outcomes. Thus, optimal evaluation among the suitable strategies is crucial in deciding which patients should be selected for the neoadjuvant approach. METHODS: A literature search was conducted in the Embase, Medline, and Cochrane electronic libraries. CONCLUSION: The evaluation of tumor and LN staging and, hence, stratifying BC recurrence risk are decisive factors in guiding clinicians to optimize treatment decisions between the neoadjuvant versus adjuvant approaches. For each individual case, it is important to consider the most likely postsurgical outcome, since, if the patient does not obtain pCR following neoadjuvant treatment, they are eligible for adjuvant T-DM1 in the case of residual disease. This review of HER2-positive female BC outlines suitable neoadjuvant and adjuvant systemic treatment strategies for guiding clinical decision making around the selection of an appropriate therapy.
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BACKGROUND: Neither paclitaxel plus trastuzumab (P-H) nor docetaxel-cyclophosphamide plus trastuzumab (TC-H) have been prospectively compared in HER2-positive early-stage breast cancer (EBC). A randomized trial was performed to assess the feasibility of a larger study. METHODS: Lower-risk HER2-positive EBC patients were randomized to either P-H or TC-H treatment arms. The co-primary feasibility outcomes were: ≥75% patient acceptability rate, active trial participation of ≥50% of medical oncologists, ≥75% and ≥90% treatment completion, and receipt rate of planned cycles of chemotherapy, respectively. SECONDARY OUTCOMES: Febrile neutropenia (FN) rate, treatment-related hospitalizations, health-related quality of life (HR-QoL) questionnaires. Analyses were performed by per protocol and intention-to-treat. RESULTS: Between May 2019 and March 2021, 49 of 52 patients agreed to study participation (94% acceptability rate). Fifteen (65%) of 23 medical oncologists approached patients. Rates of FN were higher (8.3% vs. 0%) in the TC-H vs. P-H arm. Median (IQR) changes in scores from baseline in FACT-Taxane Trial Outcome Index at 24 weeks were -4 (-10, -1) vs. -6.5 (-15, -2) for TC-H and P-H arms, respectively. CONCLUSIONS: A randomized trial comparing P-H and TC-H was feasible. Expansion to a larger trial would be feasible to explore patient-reported outcomes of these adjuvant HER2 chemotherapy regimens.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Calidad de Vida , Nivel de Atención , Quimioterapia Adyuvante , Trastuzumab/uso terapéuticoRESUMEN
BACKGROUND: We sought to estimate the proportion of patients with cancer treated with immune checkpoint inhibitors (ICI) who die soon after starting ICI in the real world and examine factors associated with early mortality (EM). METHODS: We conducted a retrospective cohort study using linked health administrative data from Ontario, Canada. EM was defined as death from any cause within 60 days of ICI initiation. Patients with melanoma, lung, bladder, head and neck, or kidney cancer treated with ICI between 2012 and 2020 were included. RESULTS: A total of 7126 patients treated with ICI were evaluated. Fifteen percent (1075 of 7126) died within 60 days of initiating ICI. The highest mortality was observed in patients with bladder and head and neck tumors (approximately 21% each). In multivariable analysis, previous hospital admission or emergency department visit, prior chemotherapy or radiation therapy, stage 4 disease at diagnosis, lower hemoglobin, higher white blood cell count, and higher symptom burden were associated with higher risk of EM. Conversely, patients with lung and kidney cancer (compared with melanoma), lower neutrophil to lymphocytes ratio, and with higher body mass index were less likely to die within 60 days post ICI initiation. In a sensitivity analysis, 30-day and 90-day mortality were 7% (519 of 7126) and 22% (1582 of 7126), respectively, with comparable clinical factors associated with EM identified. CONCLUSIONS: EM is common among patients treated with ICI in the real-world setting and is associated with several patient and tumor characteristics. Development of a validated tool to predict EM may facilitate better patient selection for treatment with ICI in routine practice.
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Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Pulmonares , Melanoma , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Retrospectivos , Melanoma/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Ontario/epidemiología , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Antibody-Drug conjugates (ADCs) are a relatively new class of drugs with a promise to improve the outcomes in specific cancers. By delivering the cytotoxic agent to tumor cells expressing specific antigens, ADCs achieve a better therapeutic index and more potency. ADCs have been approved for several hematological and solid malignancies, including breast, urothelial and gastric carcinoma. Recently, trastuzumab deruxtecan (TDXd) was the first ADC approved for previously treated metastatic HER2-mutant non-small cell lung cancer (NSCLC). Many promising ADCs are in the pipeline for clinical development in non-small cell lung cancer, including sacituzumab govitecan, patritumab deruxtecan, datopotamab deruxtecan and tusamitamab ravtansine. There is a hope that these drugs would cater to the unmet need of specific patient populations, including patients with currently untargetable mutations. We hope these drugs, e.g., TROP2 targeted ADCs, will also give more options for therapy in NSCLC to improve outcomes for patients. In this comprehensive review, we will be discussing the recent evidence including targets, efficacy and the safety of newer ADC candidates in NSCLC. We will also briefly discuss the specific toxicities, novel biomarkers, overcoming resistance mechanisms, challenges and the way forward, as these new ADCs and combinations find a way into the clinical practice.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Inmunoconjugados , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Inmunoconjugados/uso terapéuticoRESUMEN
Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways have demonstrated promising results for treatment of advanced non-small cell lung cancer. We conducted a systematic review and meta-analysis to assess the efficacy and toxicity of the combined treatment with EGFR tyrosine kinase inhibitors (TKIs) and VEGF blockade for patients with advanced non-small cell lung cancer harboring activating EGFR mutations, in comparison to EGFR TKIs alone. The electronic databases were searched for relevant randomized trials between 2000 and 2022. The primary endpoints were overall survival (OS) and progression-free survival. Secondary endpoints included objective response rate (ORR), disease control rate, and grade ≥3 adverse events (AEs). The pooled hazard ratios (HR) and odds ratios were meta-analyzed using the generic inverse variance and the Mantel-Haenszel methods. A total of 1528 patients from 8 trials were evaluated for analyses. The combination treatment decreased the risk of disease progression by 37% (HR=0.63; 95% CI, 0.56 to 0.72) but had no added benefit on OS compared with EGFR inhibition alone (HR=0.90; 95% CI, 0.76 to 1.05). There was no significant difference in objective response rate or disease control rate between treatments. There was a significantly increased number of AEs reported in the dual treatment arm (odds ratio=3.02; 95% CI, 1.71 to 5.31), with proteinuria and hypertension being the most significantly increased AEs. This meta-analysis suggests combined inhibition of EGFR and VEGF pathways significantly improves progression-free survival, with no OS benefit, and increases AEs. Mature OS data are needed along with results from more trials exploring this strategy with third-generation EGFR TKIs to strengthen these results.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Factor A de Crecimiento Endotelial Vascular , Antineoplásicos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores ErbB/genética , Factores de Crecimiento Endotelial Vascular/genética , Factores de Crecimiento Endotelial Vascular/uso terapéutico , MutaciónRESUMEN
BACKGROUND: Our aim was to establish if presence of circulating tumor cells (CTCs) predicted worse outcome in patients with non-metastatic esophageal cancer undergoing tri-modality therapy. METHODS: We prospectively collected CTC data from patients with operable non-metastatic esophageal cancer from April 2009 to November 2016 enrolled in our QUINTETT esophageal cancer randomized trial (NCT00907543). Patients were randomized to receive either neoadjuvant cisplatin and 5-fluorouracil (5-FU) plus radiotherapy followed by surgical resection (Neoadjuvant) or adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy following surgical resection (Adjuvant). CTCs were identified with the CellSearch® system before the initiation of any treatment (surgery or chemoradiotherapy) as well as at 6-, 12-, and 24-months post-treatment. The threshold for CTC positivity was one and the findings were correlated with patient prognosis. RESULTS: CTC data were available for 74 of 96 patients and identified in 27 patients (36.5%) at a median follow-up of 13.1months (interquartile range:6.8-24.1 months). Detection of CTCs at any follow-up visit was significantly predictive of worse disease-free survival (DFS;hazard ratio [HR]: 2.44; 95% confidence interval [CI]: 1.41-4.24; p=0.002), regional control (HR: 6.18; 95% CI: 1.18-32.35; p=0.031), distant control (HR: 2.93; 95% CI: 1.52-5.65;p=0.001) and overall survival (OS;HR: 2.02; 95% CI: 1.16-3.51; p=0.013). After adjusting for receiving neoadjuvant vs. adjuvant chemoradiotherapy, the presence of CTCs at any follow-up visit remained significantly predictive of worse OS ([HR]:2.02;95% [Cl]:1.16-3.51; p=0.013) and DFS (HR: 2.49;95% Cl: 1.43-4.33; p=0.001). Similarly, any observed increase in CTCs was significantly predictive of worse OS (HR: 3.14; 95% CI: 1.56-6.34; p=0.001) and DFS (HR: 3.34; 95% CI: 1.67-6.69; p<0.001). CONCLUSION: The presence of CTCs in patients during follow-up after tri-modality therapy was associated with significantly poorer DFS and OS regardless of timing of chemoradiotherapy.
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Neoplasias Esofágicas , Células Neoplásicas Circulantes , Cisplatino/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Humanos , Células Neoplásicas Circulantes/patología , PronósticoRESUMEN
BACKGROUND: We compared the health-related quality of life (HRQOL) in patients undergoing trimodality therapy for resectable stage I-III esophageal cancer. METHODS: A total of 96 patients were randomized to standard neoadjuvant cisplatin and 5-fluorouracil chemotherapy plus radiotherapy (neoadjuvant) followed by surgical resection or adjuvant cisplatin, 5-fluorouracil, and epirubicin chemotherapy with concurrent extended volume radiotherapy (adjuvant) following surgical resection. RESULTS: There was no significant difference in the functional assessment of cancer therapy-esophageal (FACT-E) total scores between arms at 1 year (p = 0.759) with 36% versus 41% (neoadjuvant vs. adjuvant), respectively, showing an increase of ≥15 points compared to pre-treatment (p = 0.638). The HRQOL was significantly inferior at 2 months in the neoadjuvant arm for FACT-E, European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-OG25), and EuroQol 5-D-3 L in the dysphagia, reflux, pain, taste, and coughing domains (p < 0.05). Half of patients were able to complete the prescribed neoadjuvant arm chemotherapy without modification compared to only 14% in the adjuvant arm (p < 0.001). Chemotherapy related adverse events of grade ≥2 occurred significantly more frequently in the neoadjuvant arm (100% vs. 69%, p < 0.001). Surgery related adverse events of grade ≥2 were similar in both arms (72% vs. 86%, p = 0.107). There were no 30-day mortalities and 2% vs. 10% 90-day mortalities (p = 0.204). There were no significant differences in either overall survival (OS) (5-year: 35% vs. 32%, p = 0.409) or disease-free survival (DFS) (5-year: 31% vs. 30%, p = 0.710). CONCLUSION: Trimodality therapy is challenging for patients with resectable esophageal cancer regardless of whether it is given before or after surgery. Newer and less toxic protocols are needed.
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Neoplasias Esofágicas , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante/métodos , Cisplatino/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/cirugía , Fluorouracilo/uso terapéutico , Humanos , Terapia Neoadyuvante/métodos , Calidad de Vida , Resultado del TratamientoRESUMEN
INTRODUCTION: The introduction of immunotherapy (IO) in the treatment of patients with cancer has significantly improved clinical outcomes. Population level information on actual IO utilization is limited. METHODS: We conducted a retrospective cohort study using provincial health administrative data from Ontario, Canada to: (1) assess the extent of IO use from 2011 (pre-IO funding) to 2019; and (2) identify factors associated with IO use in patients with advanced cancers for which IO is reimbursed including melanoma, bladder, lung, head and neck, and kidney tumors. The datasets were linked using a unique encoded identifier. A Fine and Gray regression model with death as a competing risk was used to identify factors associated with IO use. RESULTS: Among 59 510 patients assessed, 8771 (14.7%) received IO between 2011 and 2019. Use of IO increased annually from 2011 (3.3%) to 2019 (39.2%) and was highest in melanoma (52%) and lowest in head and neck cancer (6.6%). In adjusted analysis, factors associated with lower IO use included older age (hazard ratio (HR) 0.91 (95% CI, 0.89-0.93)), female sex (HR 0.85 (95% CI, 0.81-0.89)), lower-income quintile, hospital admission (HR 0.78 (95% CI, 0.75-0.82)), high Charlson score and de novo stage 4 cancer. IO use was heterogeneous across cancer centers and regions. CONCLUSION: IO utilization for advanced cancers rose substantially since initial approval albeit use is associated with patient characteristics and system-level factors even in a universal healthcare setting. To optimize IO utilization in routine practice, survival estimates and potential inequity in access should be further investigated and addressed.
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Neoplasias de Cabeza y Cuello , Melanoma , Femenino , Humanos , Factores Inmunológicos , Inmunoterapia , Ontario/epidemiología , Estudios RetrospectivosRESUMEN
INTRODUCTION: Blood-based liquid biopsies examining circulating tumour DNA (ctDNA) have increasing applications in non-small cell lung cancer (NSCLC). Limitations in sensitivity remain a barrier to ctDNA replacing tissue-based testing. We hypothesized that testing immediately after starting treatment would yield an increased abundance of ctDNA in plasma because of tumor lysis, allowing for the detection of genetic alterations that were occult in baseline testing. METHODS: Three prospective cohorts of patients with stage III/IV NSCLC were enrolled. Cohort 1 (C1) contained patients starting platinum doublet chemoradiation (n = 10) and cohort 2 (C2) initiating platinum doublet cytotoxic chemotherapy ± immunotherapy (n = 10). Cohort 3 (C3) contained patients receiving palliative radiation. Two baseline samples were collected. In C1 and C2, subsequent samples were collected 3, 6, 24 and 48 h post initiation of chemotherapy. Patients in C3 had samples collected immediately prior to the next three radiotherapy fractions. Samples were analyzed for ctDNA using the 36-gene amplicon-based NGS Inivata InVisionFirst®-Lung assay. RESULTS: A total of 40 patients were enrolled. Detectable ctDNA was present at baseline in 32 patients (80%), 4 additional patients (50%) had detectable ctDNA in post-treatment samples. Seven patients with detectable ctDNA at baseline (23%) had new genetic alterations detected in post-treatment samples. Mutant molecule numbers increased with treatment in 24 of 31 (77%) pts with detectable ctDNA. ctDNA levels peaked a median of 7 h (IQR:2-26 h) after the initiation of chemotherapy and a median of 2 days (IQR:1-3 days) after radiation was commenced. CONCLUSION: ctDNA levels increase in the hours to days after starting treatment. ctDNA testing in the acute post-treatment phase can yield results that were not evident in pre-treatment testing. Application of this principle could improve ctDNA utility as an alternate to tissue-based testing and improve sensitivity for the detection of treatment-resistant clones.(NCT03986463).
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BACKGROUND: The use of endocrine therapy for early-stage breast cancer, particularly aromatase inhibitor therapy has been associated with an increased risk of osteoporosis and fracture in clinical trials. We sought to validate this observation in real-world practice. METHODS: We used health administrative data collected from post-menopausal women (aged ≥66 years) who were diagnosed with breast cancer and started on adjuvant endocrine therapy from 2005 to 2012. Patients were classified by use of either an aromatase inhibitor or tamoxifen and followed until 2017 for a new diagnosis of an osteoporotic fracture. A multivariable analysis using a Cox proportional hazards model was adjusting for age, medical co-morbidities, medication use and duration of endocrine therapy. RESULTS: We identified 12,077 patients of whom 73% were treated with an aromatase inhibitor as compared to 27% with tamoxifen. Our multivariable analysis did not demonstrate any significant difference in the rate of osteoporotic fracture between patients treated with an aromatase inhibitor when compared with tamoxifen [Hazard ratio (HR) = 1.09; 95% confidence interval (CI) = 0.96-1.23, p-value = 0.18]. The 5-year rate of osteoporotic fracture for patients treated with either an aromatase inhibitor or tamoxifen was 7.5% and 6.9%, respectively. A completed sensitivity analysis did observe a decreased risk of fracture associated with tamoxifen usage over time. CONCLUSION: We could not detect a significant difference in the rate of osteoporotic fracture among patients treated with an aromatase inhibitor versus tamoxifen. Nonetheless, the risk with tamoxifen was numerically lower and significantly decreased when accounting for total duration of endocrine therapy.
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Neoplasias de la Mama , Fracturas Osteoporóticas , Antineoplásicos Hormonales/efectos adversos , Inhibidores de la Aromatasa/efectos adversos , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/epidemiología , Quimioterapia Adyuvante , Femenino , Humanos , Ontario/epidemiología , Fracturas Osteoporóticas/inducido químicamente , Fracturas Osteoporóticas/tratamiento farmacológico , Fracturas Osteoporóticas/epidemiología , Posmenopausia , Tamoxifeno/efectos adversosRESUMEN
We have previously found that TdT-interacting factor 1 (TdIF1) is a potential oncogene expressed in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. However, its exact mechanism is still unclear. The lysine-specific demethylase 1 (LSD1) is a crucial mediator of the epithelial-mesenchymal transition (EMT), an important process triggered during cancer metastasis. Here, we confirm that TdIF1 is highly expressed in NSCLC and related to lymph node metastasis through The Cancer Genome Atlas (TCGA) analysis of clinical samples. Silencing TdIF1 can regulate the expression of EMT-related factors and impair the migration and invasion ability of cancer cells in vitro. An analysis of tumor xenografts in nude mice confirmed that silencing TdIF1 inhibits tumor growth. Furthermore, we determined the interaction between TdIF1 and LSD1 using immunoprecipitation. Chromatin immunoprecipitation (ChIP) revealed that TdIF1 was enriched in the E-cadherin promoter region. The knockdown of TdIF1 repressed the enrichment of LSD1 at the E-cadherin promoter region, thereby regulating the level of promoter histone methylation and modulating E-cadherin transcription activity, ultimately leading to changes in EMT factors and cancer cell migration and invasion ability. The LSD1 inhibitor and TdIF1 knockdown combination showed a synergistic effect in inhibiting the growth, migration, and invasion of NSCLC cells. Taken together, this is the first demonstration that TdIF1 regulates E-cadherin transcription by recruiting LSD1 to the promoter region, thereby promoting EMT and tumor metastasis and highlighting the potential of TdIF1 as a therapeutic target for NSCLC.
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Cadherinas/genética , Proteínas de Unión al ADN/metabolismo , Desmetilación , Transición Epitelial-Mesenquimal/genética , Histona Demetilasas/metabolismo , Histonas/metabolismo , Neoplasias Pulmonares/genética , Regiones Promotoras Genéticas , Factores de Transcripción/metabolismo , Animales , Cadherinas/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular/genética , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Neoplasias Pulmonares/patología , Lisina/metabolismo , Metilación , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la Neoplasia , Unión ProteicaRESUMEN
BACKGROUND: The use of immune checkpoint inhibitors (ICIs) has become standard therapy in many tumor sites. The aim of this study is to systematically review the literature to determine whether the incidence of immune-related adverse events (irAEs) after the use of ICIs is associated with clinical outcomes in all solid malignancies. METHODS: Embase and PubMed were searched from January 1st, 2000 until March 14, 2020 for relevant studies assessing the relationship between irAEs and treatment efficacy. Outcome measures of interest included: incidence of irAEs, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Of 3384 unique citations, 51 studies met inclusion criteria. Studies included melanoma (n = 21), lung (n = 19), renal (n = 4), urothelial (n = 1), head and neck (n = 2) and gastrointestinal cancers (n = 1). In patients with metastatic melanoma (n = 1474), the development of irAEs (irAE + versus irAE-) was associated with better weighted average OS (15.24 months (95% CI 9.95 to 20.5) versus 8.94 months (95% CI 7.76 to 10.1), HR = 0.46 (n = 640, CI 0.35-0.62, p < 0.00001), PFS (17.61 months (95% CI 10.1 to 25.1) versus 2.23 months (95% CI 1.77 to 2.68), HR = 0.51 (n = 1763, CI 0.42-0.63, p < 0.00001), and ORR (37.67% (95% CI 32.8 to 42.5) versus. 23.44% (95% CI 17.8 to 29.1). Similarly, in lung cancer patients, the ORR (irAE + versus. irAE-) was 41.49% (95% CI 36.5 to 46.5) versus 18.01% (95% CI 13.5 to 22.6). The weighted average PFS and OS were 8.97 months (95% CI 7.14 to 10.8) versus 3.06 months (95% CI 2.4 to 3.72) with HR = 0.46 (n = 1575, CI 0.39-0.54, p < 0.00001) and 19.07 months (95% CI 14.3 to 23.8) versus 7.45 months (95% CI 5.34 to 9.56) HR = 0.40 (n = 1085, CI 0.30-0.51, p < 0.00001), respectively. Improved treatment efficacy in patients who developed irAEs was also seen in renal cell carcinoma, urothelial and head and neck cancers. Notably, grade 3 or 4 irAEs were associated with increased ORR but worse OS. CONCLUSION: A positive association was noted between the development of irAEs and ORR, PFS, and OS in patients treated with ICIs, irrespective of disease site, type of ICI and irAE. Grade 3 or higher toxicities resulted in better ORR, but worse OS.
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Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Humanos , Neoplasias/inmunología , Análisis de SupervivenciaRESUMEN
BACKGROUND: Everolimus plus exemestane is approved for the treatment of hormone receptor-positive metastatic breast cancer (MBC) after progression on nonsteroidal aromatase inhibitors. The role of everolimus is less well defined in other breast cancer phenotypes and in combination with other drugs. OBJECTIVES: We conducted a systematic review and meta-analysis to assess the efficacy and safety of adding everolimus to standard of care (SoC) in MBC regardless of tumor phenotype and treatment type. METHODS: The electronic databases PubMed and EMBASE were searched for eligible randomized trials. Pooled hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) and pooled risk ratios (RR) and odds ratios for objective response rates, disease control rate (DCR), and grade 3 or higher toxicity were meta-analyzed. Subgroup analyses compared survival outcomes by tumor phenotype. RESULTS: Data from 2826 patients from eight trials were analyzed. The addition of everolimus to SoC reduced the risk of disease progression by 29% (HR 0.71; 95% confidence interval [CI] 0.56-0.90). This did not translate into an OS benefit (HR 0.95; 95% CI 0.80-1.13). In addition, everolimus improved the DCR (RR 0.82; 95% CI 0.68-0.98), whereas it increased the risk of developing grade 3 or higher toxicity. The PFS benefit was more prominent for patients with hormone receptor-positive (+)/human epidermal growth factor receptor 2 (HER2)-negative (-) disease. For the HER2 (+) subgroup, the PFS benefit was restricted to patients with hormone receptor (-) disease. CONCLUSIONS: Everolimus reduces the risk of disease progression in hormone receptor (+) MBC. In patients with HER2 (+) disease, the benefit is limited for those with hormone receptor (-) disease. Given the approval and use of newer drugs in MBC, clinical trials and real-world data are needed to confirm the benefit of everolimus and define the best treatment sequence strategy to adopt in that setting.
Asunto(s)
Antineoplásicos/uso terapéutico , Everolimus/uso terapéutico , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Everolimus/farmacología , Femenino , HumanosRESUMEN
One year of adjuvant trastuzumab is considered the standard treatment for patients with HER2 positive breast cancer. However, a shorter duration of trastuzumab may be associated with reduced costs and side effects. Results from randomized trials with diverse non-inferiority margins comparing one year to a shorter duration of adjuvant trastuzumab are not consistent and have not been systematically reviewed using a non-inferiority meta-analysis approach. We conducted a systematic review and meta-analysis of randomized trials to assess whether a shorter duration of adjuvant trastuzumab was non-inferior to one year of treatment or not. The non-inferiority margin for the meta-analysis was pre-defined as the median of the margins of all the trials included. Data of 11,376 patients from 5 trials were analyzed. Non-inferiority margins in included studies varied from 1.15 to 1.53 with median of 1.29 for HR of DFS. A shorter duration of trastuzumab was non-inferior to one year of therapy for DFS (HR 1.13, 95%CI 1.03-1.24) but inconclusive for OS (HR 1.14, 95%CI 1.00-1.30). In a subgroup analysis for DFS outcome, shorter therapy was non-inferior in patients with ER positive disease (HR 1.10, 95%CI 0.95-1.28) and those with sequential therapy (HR 0.97, 95%CI 0.75-1.27) and when the duration of treatment was 6 months (HR 1.09, 95%CI 0.98-1.22). Although a shorter duration of adjuvant trastuzumab was non-inferior to one year of therapy for DFS in patients with HER2 positive breast cancer based on our HR margin of 1.29, any benefit of a shorter duration comes at a loss of efficacy with an increase in absolute risk up to 3.9% for 5 year DFS. Whether the potential increased risk is clinically acceptable for the benefits of a shorter duration remains debatable.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante/métodos , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Quimioterapia Adyuvante/mortalidad , Supervivencia sin Enfermedad , Estudios de Equivalencia como Asunto , Femenino , Humanos , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: The association between endocrine therapy and risk of dementia remains uncertain. We investigated the association between adjuvant endocrine therapy for breast cancer and risk of developing dementia in a real-world, population-based study. METHODS: We used health administrative data collected from post-menopausal women (aged ≥66â¯years) who were diagnosed with breast cancer and started on adjuvant endocrine therapy from 2005 to 2012 with follow-up until 2017. Patients were classified by the use of either an aromatase inhibitor or tamoxifen and followed to estimate the unadjusted cumulative incidence of developing dementia. A multivariable Cox proportional hazards model was created adjusting for age, income quintile, medical co-morbidities, and duration of endocrine therapy. RESULTS: We identified 12,077 patients of whom 73% were treated with an aromatase inhibitor and 27% with tamoxifen. Our multivariable analysis showed a lower rate of dementia in patients treated with an aromatase inhibitor as compared to tamoxifen [Hazard ratio (HR)â¯=â¯0.88, 95% confidence interval (CI): 0.78-0.98, p-valueâ¯=â¯.02) at a median follow-up of 5.9â¯years. The 5-year dementia rate among patient treated with either an aromatase inhibitor or tamoxifen was 7.4% and 9.2% respectively. Older age, previous history of ischemic heart disease, diabetes, hypertension and history of stroke were all significantly associated with the development of dementia. CONCLUSION: Aromatase inhibitor therapy was associated with a decreased incidence of dementia as compared to treatment with tamoxifen among post-menopausal women with early stage breast cancer. Further prospective studies with longer-term follow-up investigating the neurocognitive effects of endocrine therapy are warranted.