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The advancements in the detection and characterization of circulating tumor DNA (ctDNA) have revolutionized precision medicine and are likely to transform standard clinical practice. The non-invasive nature of this approach allows for molecular profiling of the entire tumor entity, while also enabling real-time monitoring of the effectiveness of cancer therapies as well as the identification of resistance mechanisms to guide targeted therapy. Although the field of ctDNA studies offers a wide range of applications, including in early disease, in this review we mainly focus on the role of ctDNA in the dynamic molecular characterization of unresectable locally advanced and metastatic BC (mBC). Here, we provide clinical practice guidance for the rapidly evolving field of molecular profiling of mBC, outlining the current landscape of liquid biopsy applications and how to choose the right ctDNA assay. Additionally, we underline the importance of exploring the clinical relevance of novel molecular alterations that potentially represent therapeutic targets in mBC, along with mutations where targeted therapy is already approved. Finally, we present a potential roadmap for integrating ctDNA analysis into clinical practice.
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Introduction: Prognosis of patients diagnosed with HER2+ early breast cancer (eBC) has substantially improved, but distant recurrences impacting quality of life and survival still occur. One treatment option for extended adjuvant treatment of patients with HER2+/HR+ eBC is neratinib, available in Europe for patients who completed adjuvant trastuzumab-based therapy within 1 year. The ELEANOR study is investigating the real-world use of neratinib in Germany, Austria, and Switzerland. Results from an interim analysis of the first 200 patients observed for ≥3 months are reported. Methods: The primary objective of this prospective, multicenter, observational study is to assess patient adherence to neratinib (defined as the percentage of patients taking neratinib on ≥75% prescribed days). Secondary objectives are patient characteristics and treatment outcomes. Results: At cut-off (May 2, 2022), a total of 202 patients had been observed for ≥3 months, with neratinib treatment documented for 187 patients (median age: 53.0 years; 67.9% at increased risk of disease recurrence). In total, 151 (80.7%) patients had received prior neoadjuvant treatment; of these, 82 (54.3%) patients achieved a pathologically complete response. Neratinib was initiated at a median 3.6 months after trastuzumab-based treatment, with 36.4% starting at a dose <240 mg/day. Treatment is ongoing for 46.0% of patients, with median treatment duration of 11.2 (interquartile range 0.9-12.0) months. Diarrhea was the most common adverse event (78.6% any grade, 20.3% grade ≥3); pharmacologic prophylaxis was used in 85.6% of patients. Conclusions: The pattern of anti-HER2 pretreatment observed reflected the current treatment for HER2+/HR+ eBC in Germany, Austria, and Switzerland. These interim results suggest that neratinib as an extended adjuvant is a feasible option after various anti-HER2 pretreatments and that its tolerability can be managed and improved with proactive diarrhea management.
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Approximately 15% of newly diagnosed breast cancer patients have neither hormone receptors expression nor HER2 overexpression and/or HER2/neu gene amplification. This subtype of breast cancer is known as Triple Negative Breast Cancer (TNBC), and carries a significantly elevated risk of local and distant recurrence. In comparison with other breast cancer subtypes, there is a higher rate of visceral and brain metastases. The majority of metastases of TNBC are diagnosed within three years after initial breast cancer diagnosis. While there have been major advances in hormone-receptor- positive and in human epidermal growth factor receptor 2 (HER2)-positive disease over the past two decades, only limited improvements in outcomes for patients with triple negative breast cancer (TNBC) have been observed. A group of Austrian breast cancer specialists therefore convened an expert meeting to establish a comprehensive clinical risk-benefit profile of available mTNBC therapies and discuss the role sacituzumab govitecan may play in the treatment algorithm of the triple-negative breast cancer patients.
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Background: Age-standardized mortality rates for metastatic colorectal cancer (mCRC) are highest among elderly patients. In current clinical guidelines, treatment recommendations for this patient population are based on a limited number of clinical trials. Patients and methods: In this monocentric, retrospective analysis we characterized patients aged ≥70 years undergoing systemic therapy for mCRC and overall survival (OS) was investigated. Results: We included 117 unselected, consecutive mCRC patients aged ≥70 years undergoing systemic therapy for mCRC between February 2009 and July 2022. Median OS was 25.6 months (95% CI: 21.8-29.4). The median age was 78 years (range: 70-90) and 21%, 48%, 26% and 5% had an ECOG performance score of 0, 1, 2, and 3, respectively. The median number of systemic therapy lines was 2 (range: 1-5). The choice of first-line chemotherapy backbone (doublet/triplet versus mono) did not impact OS (HR: 0.83, p=0.50) or the probability of receiving subsequent therapy (p=0.697). Metastasectomy and/or local ablative treatment in the liver, lung, peritoneum and/or other organs were applied in 26 patients (22%) with curative intent. First-line anti-EGFR-based therapy showed a trend towards longer OS compared to anti-VEGF-based therapy or chemotherapy alone in left-sided mCRC (anti-EGFR: 39.3 months versus anti-VEGF: 27.3 months versus chemotherapy alone: 13.8 months, p=0.105). In multivariable analysis, metastasectomy and/or local ablative treatment with curative intent (yes versus no, HR: 0.22, p<0.001), the ECOG performance score (2 versus 0, HR: 3.07, p=0.007; 3 versus 0, HR: 3.66, p=0.053) and the presence of liver metastases (yes versus no, HR: 1.79, p=0.049) were independently associated with OS. Conclusions: Our findings corroborate front-line monochemotherapy in combination with targeted therapy as the treatment of choice for elderly mCRC patients with palliative treatment intent. Metastasectomy and/or local ablative treatment with curative intent are feasible and may improve OS in selected elderly mCRC patients.
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BACKGROUND AND PURPOSE: Our study aimed to assess whether quantitative pretreatment 18F-FDG-PET/CT parameters could predict prognostic clinical outcome of recurrent NSCLC patients who may benefit from ablative reirradiation. MATERIALS AND METHODS: Forty-eight patients with recurrent NSCLC of all UICC stages who underwent ablative thoracic reirradiation were analyzed. Twenty-nine (60%) patients received immunotherapy with or without chemotherapy in addition to reirradiation. Twelve patients (25%) received reirradiation only and seven (15%) received chemotherapy and reirradiation. Pretreatment 18-FDG-PET/CT was mandatory in initial diagnosis and recurrence, based on which volumetric and intensity quantitative parameters were measured before reirradiation and their impact on overall survival, progression-free survival, and locoregional control was assessed. RESULTS: With a median follow-up time of 16.7 months, the median OS was 21.8 months (95%-CI: 16.2-27.3). On multivariate analysis, OS and PFS were significantly influenced by MTV (p < 0.001 for OS; p = 0.006 for PFS), TLG (p < 0.001 for OS; p = 0.001 for PFS) and SUL peak (p = 0.0024 for OS; p = 0.02 for PFS) of the tumor and MTV (p = 0.004 for OS; p < 0.001 for PFS) as well as TLG (p = 0.007 for OS; p = 0.015 for PFS) of the metastatic lymph nodes. SUL peak of the tumor (p = 0.05) and the MTV of the lymph nodes (p = 0.003) were only PET quantitative parameters that significantly impacted LRC. CONCLUSION: Pretreatment tumor and metastastic lymph node MTV, TLG and tumor SUL peak significantly correlated with clinical outcome in recurrent NSCLC patients treated with reirradiation-chemoimmunotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Reirradiação , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Prognóstico , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Biomarcadores , Estudos Retrospectivos , Carga Tumoral , Compostos Radiofarmacêuticos , GlicóliseRESUMO
BACKGROUND: The widespread adoption of adjuvant bisphosphonate therapy for postmenopausal early breast cancer (EBC) patients was based on results of the Early Breast Cancer Trialist Group (EBCTCG) meta-analysis. Despite multiple regimens evaluated, there was no signal of varying efficacy with type, dose/dose intensity of bisphosphonate administration. We evaluated the effect of early treatment cessation using long-term outcome data from the ABCSG-12 trial. PATIENTS AND METHODS: ABCSG-12 randomized 1803 hormone-receptor positive EBC patients on ovarian suppression between 1999 and 2006 to receive 4 mg zoledronic acid 6-monthly or not (and tamoxifen or anastrozole, 2:2 factorial design). In the current study, we evaluated whether the number of zoledronate infusions had an impact on breast cancer-specific outcomes. We hypothesized that amongst patients who received at least one zoledronate infusion, the number of infusions had no effect on outcomes. Time-to-event endpoints were analysed with Cox models and Kaplan Meier curves starting from a 3-year landmark. BMD analysis was restricted to patients who participated in the BMD sub-study. RESULTS: 725 patients who received at least one zoledronate infusion were included in the time-to-event analysis. There was no statistically significant difference in disease-free or overall survival in the patients who received ≤6 zoledronate infusions (n = 170) compared to those who received ≥7 zoledronate infusions (n = 555). CONCLUSIONS: Comparable to efforts to de-escalate treatment duration in metastatic bone disease, there was no evidence to indicate that a reduced number of zoledronate infusions is associated with reduced adjuvant efficacy. Further studies to define optimal regimens of adjuvant bone-targeted therapies are required.
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Neoplasias da Mama , Feminino , Humanos , Adjuvantes Imunológicos/uso terapêutico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Difosfonatos , Resultado do Tratamento , Ácido Zoledrônico/uso terapêuticoRESUMO
PURPOSE: Perioperative chemotherapy with FLOT constitutes a standard of care approach for locally advanced, resectable gastric or gastro-esophageal junction (GEJ) cancer. We aimed at investigating anthropometric, CT-based and FDG-PET-based body composition parameters and dynamics during this multidisciplinary approach and the impact on clinical outcomes. METHODS: This retrospective, single-center study was based on medical records and (FDG-PET)-CT images among gastric/GEJ cancer patients undergoing perioperative FLOT chemotherapy. RESULTS: Between 2016 and 2021, 46 gastric/GEJ cancer patients started perioperative FLOT at our tertiary cancer center (Salzburg, Austria). At a median follow-up of 32 months median PFS was 47.4 months and median OS was not reached. The skeletal muscle index (SMI, cm2/m2) turned out to be the only body composition parameter with a statistically significant decrease during pre-operative FLOT (51.3 versus 48.8 cm2/m2, p = 0.02). Neither pre-FLOT body mass index (BMI), nor SMI had an impact on the duration of pre-operative FLOT, the time interval from pre-operative FLOT initiation to surgery, the necessity of pre-operative or post-operative FLOT de-escalation or the likelihood of the start of postoperative chemotherapy. Pre-FLOT BMI (overweight versus normal, HR: 0.11, 95% CI: 0.02-0.65, p = 0.02) and pre-FLOT SMI (sarcopenia versus no sarcopenia, HR: 5.08, 95% CI: 1.27-20.31, p = 0.02) were statistically significantly associated with PFS in the multivariable analysis. CONCLUSION: The statistically significant SMI loss during pre-operative FLOT and the meaningful impact of baseline SMI and BMI on PFS argue for the implementation of a nutritional screening and support program prior to the initiation of pre-operative FLOT in clinical routine.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Estudos Retrospectivos , Fluordesoxiglucose F18 , Avaliação Nutricional , Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estado Nutricional , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Junção Esofagogástrica/cirurgia , Composição CorporalRESUMO
In the past 12 months a plethora of relevant novel data for the treatment of metastatic HER2 positive breast cancer were published. To bring this new evidence into a clinical perspective, a group of Austrian breast cancer specialists updated their previously published treatment algorithm for those patients. For this consensus paper a total of eight scenarios were developed in which treatment strategies appropriate for specific patient profiles were evaluated. Consensus was established by detailed discussions of each scenario and by reaching full consensus.
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Neoplasias da Mama , Segunda Neoplasia Primária , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptor ErbB-2/uso terapêutico , Áustria , AlgoritmosRESUMO
Background: Associations between height, cancer risk and worse outcome have been reported for several cancers including breast cancer. We hypothesized that in breast cancer clinical trials, tall women should be overrepresented and might have worse prognosis. Methods: Data of 4,935 women, included from 1990 to 2010 in 5 trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG), were analyzed retrospectively. The primary objective was to determine differences in height distribution between the ABCSG cohort and the Austrian female population according to a cross-sectional health survey conducted by the Austrian Statistic Center in 2006 and 2007. Secondary endpoints were disease-free survival (DFS) and overall survival (OS) in different height classes and differences of body mass index (BMI) distribution. Results: Breast cancer patients in the ABCSG cohort were only slightly but statistically significantly smaller compared to unselected Austrian adult females (mean 164.3 vs. 164.8 cm; p < 0.0001) and significantly more patients were seen in the lower body height class (50 vs. 46%; p < 0.0001) when using the median as a cutoff. However, after adjustment for age, the difference in body height between the two cohorts was no longer significant (p = 0.089). DFS and OS in the two upper height groups (≥170 cm) compared to the two lowest height groups (<160 cm) was not significantly different (5-year DFS: 84.7 vs. 83.0%; HR 0.91, 95% CI 0.73-1.13, p = 0.379; 5-year OS: 94.8 vs. 91.7%; HR 0.74, 95% CI 0.55-1.00, p = 0.051). The BMI of ABCSG patients was significantly higher than in the reference population (mean BMI 24.64 vs. 23.96; p < 0.0001). Conclusions: Our results do not confirm previous findings that greater body height is associated with a higher breast cancer risk and worse outcome.
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Background: For hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC), adjuvant chemotherapy (ACT) is recommended in the case of high-risk features only. The MINDACT trial showed that patients with high clinical risk (CR) but low genomic risk (GR) defined by the 70-gene signature (MammaPrint®; 70-GS) did not benefit from ACT. In this registry, we investigated the frequency and feasibility of 70-GS and concurrent 80-gene subtyping (BluePrint®) use in HR-positive, HER2-negative EBC. Furthermore, we recorded the frequency of ACT recommendation and the adherence to it when the "MINDACT strategy" was used. Methods: This prospective registry included patients from 2 Austrian cancer centers. Similar to MINDACT, a modified version of Adjuvant!Online was used to determine CR, and 70-GC was used to determine GR in high-CR patients. ACT was recommended to patients with high CR and high GR. Results: Of 224 enrolled patients, 76 (33.9%) had high CR and 67 (88.2%) received genomic testing. Of those, 43 (64.2%) were classified as low and 24 (35.8%) as high GR, respectively. All 24 patients with high CR and GR (10.7% of all patients) received the recommendation for ACT, but ACT was started in only 15 patients (62.5%). The median time from surgery to the start of ACT was 45 days (range 32-68), and the median time from test decision to the test result was 15 days (range 9-56). Conclusion: We showed that the results of the MINDACT trial are reproducible in an Austrian population. Incorporating 70-GS into the daily clinical routine is feasible and mostly accepted by physicians for the guidance of treatment recommendations.
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BACKGROUND: Safety and efficacy of immune checkpoint inhibitors in advanced gastric or gastroesophageal junction (GEJ) cancer could be demonstrated in predominantly Asian cohorts, whereas data in Western patients outside of clinical trials are vastly missing. METHODS: In this multi-institutional retrospective analysis conducted at nine oncologic centers in Austria, we tried to assess feasibility of checkpoint inhibitors in advanced gastric/GEJ cancer in a real-world Western cohort. RESULTS: In total, data from 50 patients with metastatic gastric/GEJ cancer who received nivolumab or pembrolizumab in a palliative setting between November 2015 and April 2020 have been evaluated. The median number of previous palliative therapy lines was two. The median progression-free survival (PFS) and overall survival (OS) were 2.1 (95% CI: 1.4-2.8) and 6.3 (95% CI: 3.3-9.3) months, respectively. There was no statistically significant difference in median OS according to microsatellite or PD-L1 status. However, a trend towards prolonged PFS and OS for the microsatellite instability high subgroup could be observed. Patients with an ECOG Performance Status (PS) ≥ 2 displayed a significantly worse outcome than those with an ECOG PS ≤ 1 (p = .03). Only one patient discontinued immunotherapy due to treatment-related toxicity. CONCLUSIONS: Our results support feasibility of nivolumab and pembrolizumab in pre-treated patients with metastatic gastric and GEJ cancer in a Western real-world cohort. Further phase II/III studies are needed to confirm clinical efficacy.
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Neoplasias Esofágicas , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Gástricas , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Áustria , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologiaRESUMO
A group of Austrian breast cancer specialists met in December 2020 to establish a comprehensive clinical benefit-risk profile of available HER2-targeted therapies based on recent data and to develop an updated treatment algorithm by consensus over several months in 2021. A total of four scenarios were developed in which treatment strategies appropriate for specific patient profiles were evaluated. Consensus was established by detailed discussions of each scenario and by reaching full consensus.
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Neoplasias da Mama , Algoritmos , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Áustria , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêutico , Trastuzumab/uso terapêuticoRESUMO
PURPOSE: Accurate response assessment during neoadjuvant systemic treatment (NST) poses a clinical challenge. Therefore, a minimally invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions. EXPERIMENTAL DESIGN: We profiled 93 genes in tissue from 193 patients with early breast cancer. Patient-specific assays were designed for 145 patients to track ctDNA during NST in plasma. ctDNA presence and levels were correlated with complete pathological response (pCR) and residual cancer burden (RCB) as well as clinicopathologic characteristics of the tumor to identify potential proxies for ctDNA release. RESULTS: At baseline, ctDNA could be detected in 63/145 (43.4%) patients and persisted in 25/63 (39.7%) patients at mid-therapy (MT) and 15/63 (23.8%) patients at the end of treatment. ctDNA detection at MT was significantly associated with higher RCB (OR = 0.062; 95% CI, 0.01-0.48; P = 0.0077). Of 31 patients with detectable ctDNA at MT, 30 patients (96.8%) were nonresponders (RCB II, n = 8; RCB III, n = 22) and only one patient responded to the treatment (RCB I). Considering all 145 patients with baseline (BL) plasma, none of the patients with RCB 0 and only 6.7% of patients with RCB I had ctDNA detectable at MT, whereas 30.6% and 29.6% of patients with RCB II/III, respectively, had a positive ctDNA result. CONCLUSIONS: Overall, our results demonstrate that the detection and persistence of ctDNA at MT may have the potential to negatively predict response to neoadjuvant treatment and identify patients who will not achieve pCR or be classified with RCB II/III.
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Neoplasias da Mama , DNA Tumoral Circulante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , DNA Tumoral Circulante/genética , Feminino , Humanos , Terapia Neoadjuvante , Neoplasia Residual/patologiaRESUMO
BACKGROUND: Adjuvant aromatase inhibitors increase osteoporosis and fractures in patients with hormone receptorpositive breast cancer. We have previously reported outcomes of the ABCSG-18 (study 18 from the Austrian Breast & Colorectal Cancer Study Group) trial showing that adjuvant antireceptor activator of nuclear factor-κB ligand denosumab treatment counteracts these adverse effects and may improve outcomes. We report here the final long-term outcomes. METHODS: ABCSG-18 is a prospective, double-blind, placebo-controlled, phase 3 trial in which 3425 postmenopausal patients with early hormone receptorpositive breast cancer receiving aromatase inhibitor therapy were randomly assigned in 58 trial centers to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months. The primary end point was the time to first clinical fracture after randomization. Secondary disease outcomerelated end points were disease-free survival (DFS), bone metastasisfree survival (BMFS), and overall survival (OS). RESULTS: For this final protocol-defined analysis, median follow-up is 8 years (interquartile range, 6 to 9.6 years). There were 309 versus 368 DFS events (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.97) in the denosumab versus the placebo group, respectively, resulting in an absolute 9-year DFS benefit of 3.5 percentage points (79.4 vs. 75.9%). Adjuvant denosumab improved BMFS by 2.5 percentage points (88.9 vs. 86.4%; hazard ratio, 0.81; 95% CI, 0.65 to 1.00) and OS by 1.0 percentage point (90.9 vs. 89.9%; hazard ratio, 0.80; 95% CI, 0.64 to 1.01). No new toxicities for this dose of adjuvant denosumab were observed. CONCLUSIONS: DFS, BMFS, and OS continued to show benefit in this final long-term analysis of ABCSG-18. There were no new toxicities. (Funded by Amgen; ClinicalTrials.gov number, NCT00556374.)
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Neoplasias da Mama , Feminino , Humanos , Adjuvantes Imunológicos , Adjuvantes Farmacêuticos , Inibidores da Aromatase , Denosumab/farmacologia , Intervalo Livre de Doença , Estudos Prospectivos , Método Duplo-CegoRESUMO
BACKGROUND: About 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ hybridization. This low HER2 expression is a promising new target for antibody-drug conjugates (ADCs) currently under investigation. Until now, little is known about the frequency and the prognostic value of low HER2-expression in metastatic breast cancer (MBC). PATIENTS AND METHODS: The MBC-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT) is a multicenter nationwide ongoing registry for MBC patients in Austria. Unadjusted, univariate survival probabilities of progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method and compared by the log-rank test. Multivariable adjusted hazard ratios were estimated by Cox regression models. In this analysis, only patients with known HER2 status and available survival data were included. RESULTS: As of 11/15/2020, 1,973 patients were included in the AGMT-MBC-Registry. Out of 1,729 evaluable patients, 351 (20.3%) were HER2-positive, 608 (35.2%) were HER2-low and 770 (44.5%) were completely HER2-negative (HER2-0). Low HER2-expression was markedly more frequent in the hormone-receptor(HR)+ subgroup compared to the triple-negative subgroup (40% vs. 23%). In multivariable analysis, low HER2 expression did not significantly influence OS neither in the HR+ (HR 0.89; 95% CI 0.74-1.05; P = 0.171) nor in the triple-negative subgroup (HR 0.92; 95% CI 0.68-1.25; P = 0.585), when compared to completely HER2-negative disease. Similar results were observed when HER2 IHC 2+ patients were compared to IHC 1+ or 0 patients. CONCLUSION: Low-HER2 expression did not have any impact on prognosis of metastatic breast cancer in this real-world population.
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Neoplasias da Mama , Áustria/epidemiologia , Neoplasias da Mama/patologia , Feminino , Humanos , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Sistema de RegistrosRESUMO
BACKGROUND: Bendamustine, a medication approved for the treatment of indolent non-Hodgkin lymphoma, has already shown anticancer activity in metastatic breast cancer (MBC). Here, we present the results of a phase II trial of bendamustine in combination with capecitabine in pre-treated patients with MBC. PATIENTS AND METHODS: AGMT MBC-6 is a multicentre, open-label, single-arm phase II study in HER2-negative MBC. All patients were pre-treated with anthracyclines and/or taxans and had measurable disease. Patients received per os 1000 mg/m2 capecitabine twice daily on days 1 to 14 in combination with 80 mg/m2 bendamustine intravenously on days 1 and 8 of a 3-week cycle for a maximum of eight cycles, followed by a capecitabine maintenance therapy. The primary endpoint was overall response rate (ORR). RESULTS: From September 2013 to May 2015, 40 patients were recruited in eight Austrian centres. The median age was 60 years (range 29-77). Twenty-five per cent of patients had triple-negative breast cancer (TNBC) and 93% showed visceral involvement. With 17 partial and one complete remission, ORR was 46%. Median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI) 6.1-10.7]. The most common non-haematological adverse events (AEs) of grade 3 were hand-foot syndrome (13%), fatigue (10%), nausea (8%), and dyspnoea (8%). One grade 4 non-haematological AE (hepatic failure) and three grade 4 haematological AEs (neutropenia) were observed. One patient died of restrictive cardiomyopathy, in which a relationship to capecitabine cannot be excluded, but seems unlikely. CONCLUSION: The combination of capecitabine and bendamustine shows promising efficacy and moderate toxicity. Further evaluation of this drug combination is warranted.The clinical trial AGMT MBC-6 was registered at ClinicalTrials.gov, (https://clinicaltrials.gov/; identifier: NCT01891227).
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BACKGROUND: The addition of cisplatin or cetuximab to radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) has significantly improved the outcome. While the superiority of cisplatin over cetuximab in combination with radiotherapy has been shown in a definitive setting, we set out to compare postoperative chemoradiotherapy with cisplatin to radioimmunotherapy with cetuximab and radiotherapy alone within the Austrian head and neck cancer registry of the Working Group on Pharmaceutical Tumor Treatment (AGMT) study group. MATERIAL AND METHODS: In the AGMT head and neck cancer registry, data of 557 patients with SCCHN from five Austrian cancer centers were prospectively collected between 2012 and 2017. Of these patients 120 received postoperative chemoradiotherapy with cisplatin, 26 patients received postoperative radioimmunotherapy with cetuximab and 56 patients were treated with adjuvant radiotherapy only. Patient characteristics, stage of disease, details on treatment as well as survival were analyzed by a chart-based review. RESULTS: In patients treated with postoperative radiotherapy the addition of cisplatin significantly improved progression-free survival (PFS) and overall survival (OS) compared to cetuximab (PFS 84.2 months vs. 17.0 months, pâ¯= 0.04, OS not reached vs. 46.0 months, pâ¯= 0.02) and PFS compared to radiotherapy alone (PFS 84.2 months vs. 28.5 months, pâ¯< 0.01). Patients treated with cetuximab were significantly older and had a worse performance score than patients receiving cisplatin or radiotherapy alone. CONCLUSION: This study confirmed the importance of multimodal treatment concepts in patients with locally advanced SCCHN. Postoperative cetuximab might be an option in patients not eligible for high-dose cisplatin but cisplatin should remain the standard of care.
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Cisplatino , Neoplasias de Cabeça e Pescoço , Áustria , Cetuximab , Quimiorradioterapia , Humanos , Radioimunoterapia , Sistema de RegistrosRESUMO
BACKGROUND: The tumor-microenvironment (TME) represents an attractive therapeutic target in NSCLC and plays an important role for efficacy of cancer therapeutics. We hypothesized that upregulation of collagen synthesis might be associated with adverse outcome in NSCLC. Literature evidence suggests that renin-angiotensin system inhibitors (RASi) decrease collagen deposition. Therefore, we aimed to explore the prognostic role of RASi intake and their influence on the TME in NSCLC. METHODS: Four publicly available datasets were used to evaluate the impact of key enzymes involved in collagen biosynthesis. To investigate the influence of RASi intake on the TME and prognosis we evaluated a cohort of metastatic NSCLC patients and performed histopathological characterization of the TME. A three-dimensional microtissue in vitro model was developed to define the impact of RASi on collagen synthesis. RESULTS: Expression of three genes of the collagen synthesis pathway, ALDH18A1, PLOD2 and P4HA1, was upregulated in NSCLC compared to normal lung tissue and linked to shortened overall survival in all investigated cohorts. Together, these genes formed a 'Collagen Signature' which represents an independent unfavourable prognostic factor in two NSCLC cohorts and was linked to alterations of the extracellular matrix deposition and cell cycle pathways. In the cohort of metastatic NSCLC, RASi intake was linked to improved overall response rate and survival. Exploratory in vitro experiments revealed that RASi led to a dose dependent reduction of collagen deposition and degradation of three-dimensional lung cancer cell spheroids. CONCLUSION: We demonstrate that collagen synthesis is a key upregulated process in the NSCLC TME and its transcriptional readout, the three gene Collagen Signature is independently associated with poor outcome. Pharmacological targeting of this pathways e.g. by RASi bears potential of improving outcome in NSCLC.
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Neoplasias Pulmonares , Sistema Renina-Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Colágeno , Ácido Glutâmico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Microambiente TumoralRESUMO
BACKGROUND: For postmenopausal women with hormone-receptor-positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear. METHODS: In this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture. RESULTS: Among the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84). CONCLUSIONS: In postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620.).
Assuntos
Anastrozol/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Administração Oral , Idoso , Anastrozol/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Receptores de Estrogênio , Receptores de Progesterona , Tamoxifeno/uso terapêuticoRESUMO
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease arising from the mucosa of the upper aerodigestive tract. Despite multimodality treatments approximately half of all patients with locally advanced disease relapse and the prognosis of patients with recurrent or metastatic HNSCC is dismal. The introduction of checkpoint inhibitors improved the treatment options for these patients and pembrolizumab alone or in combination with a platinum and fluorouracil is now the standard of care for first-line therapy. However, approximately only one third of unselected patients respond to this combination and the response rate to checkpoint inhibitors alone is even lower. This shows that there is an urgent need to improve prognostication and prediction of treatment benefits in patients with HNSCC. In this review, we summarize the most relevant risk factors in the field and discuss their roles and limitations. The human papilloma virus (HPV) status for patients with oropharyngeal cancer and the combined positive score are the only biomarkers consistently used in clinical routine. Other factors, such as the tumor mutational burden and the immune microenvironment have been highly studied and are promising but need validation in prospective trials.