Multi-omic analysis identifies hypoalbuminemia as independent biomarker of poor outcome upon PD-1 blockade in metastatic melanoma

We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n = 178). An independent validation cohort (n = 79) was used to validate the performance of hypoalbuminemia compared to serum LDH (lactate dehydrogenase) levels. Pre-treatment hypoalbuminemia emerged as the strongest predictor of poor outcome for both OS (HR = 4.01, 95% CI 2.10–7.67, Cox P = 2.63e−05) and PFS (HR = 3.72, 95% CI 2.06–6.73, Cox P = 1.38e−05) in univariate analysis. In multivariate analysis, the association of hypoalbuminemia with PFS was independent of serum LDH, IFN-γ signature expression, TMB, age, ECOG PS, treatment line, treatment type (combination or monotherapy), brain and liver metastasis (HR = 2.76, 95% CI 1.24–6.13, Cox P = 0.0131). Our validation cohort confirmed the prognostic power of hypoalbuminemia for OS (HR = 1.98, 95% CI 1.16–3.38; Cox P = 0.0127) and was complementary to serum LDH in analyses for both OS (LDH-adjusted HR = 2.12, 95% CI 1.2–3.72, Cox P = 0.00925) and PFS (LDH-adjusted HR = 1.91, 95% CI 1.08–3.38, Cox P = 0.0261). In conclusion, pretreatment hypoalbuminemia was a powerful predictor of outcome in ICI in melanoma and showed remarkable complementarity to previously established biomarkers, including high LDH.</p

Is a History of Optimal Staging by Sentinel Lymph Node Biopsy in the Era Prior to Adjuvant Therapy Associated with Improved Outcome Once Melanoma Patients have Progressed to Advanced Disease?

Introduction: Sentinel lymph node biopsy (SLNB) is important for staging in patients with primary cutaneous melanoma. Did having previously undergone SLNB also affect outcomes in patients once they have progressed to metastatic melanoma in the era prior to adjuvant therapy?Methods: Data were retrieved from the Dutch Melanoma Treatment Registry, a prospectively collected, nationwide database of patients with unresectable stage IIIC or IV (advanced) melanoma between 2012 and 2018. Melanoma-specific survival (MSS) was compared between patients with advanced cutaneous melanoma, previously treated with a wide local excision (WLE) or WLE combined with SLNB as initial treatment of their primary tumor. Cox regression analyses were used to analyze the influence of different variables on MSS.Results: In total, 2581 patients were included, of whom 1412 were treated with a WLE of the primary tumor alone and 1169 in whom this was combined with SLNB. At a median follow-up of 44 months from diagnosis of advanced melanoma, MSS was significantly longer in patients who had previously undergone SLNB {median 23 months (95% confidence interval [CI] 19–29) vs. 18 months (95% CI 15–20) for patients treated with WLE alone; p = 0.002}. However, multivariate Cox regression did not identify SLNB as an independent favorable prognostic factor for MSS after diagnosis of advanced melanoma.Conclusion: Prior to the availability of adjuvant systemic therapy, once patients have unresectable stage IIIC or IV (advanced) melanoma, there was no difference in disease outcome for patients who were or were not previously staged with SLNB.</p

Adjuvant treatment for melanoma in clinical practice - Trial versus reality

Background: Little is known about outcomes of adjuvant-treated melanoma patients beyond the clinical trial setting. Since 2019, adjuvant-treated melanoma patients have been registered in the DMTR, a population-based registry to monitor the quality and safety of melanoma care in the Netherlands. This study aims to describe treatment patterns, relapse, and toxicity rates of adjuvant-treated melanoma patients beyond the clinical trial setting. Methods: Analyses were performed on adjuvant-treated melanoma patients included in the DMTR. Descriptive statistics were used to analyse patient-, and treatment characteristics. A baseline registration completeness analysis was performed, and an analysis on trial eligibility in clinical practice patients. Recurrence-free survival (RFS) at 12-months was estimated with the Kaplan-Meier method. Results: A total of 641 patients were treated with adjuvant anti-PD-1 therapy. RFS at 12-months was 70.6% (95% CI, 66.9-74.6) with a median follow-up of 12.8 months. Sex, stage of disease and Breslow thickness were associated with a higher hazard for RFS. Eighteen per cent of the anti-PD-1-treated patients developed grade >= 3 toxicity. Sixty-one per cent of patients prematurely discontinued anti-PD-1 therapy. Conclusion: Adjuvant anti-PD-1 treatment of resected stage III/IV melanoma in daily practice showed slightly higher toxicity rates and more frequent premature discontinuation but similar RFS rates compared to trials. (C) 2021 The Authors. Published by Elsevier Ltd

Receptor conversion in distant breast cancer metastases : A Systematic Review and Meta-analysis

Background: In metastatic breast cancer, hormone and/or human epidermal growth factor receptor 2 (HER2)-targeted therapy decision-making is still largely based on tissue characteristics of the primary tumor. However, a change of estrogen receptor alpha (ERa), progesterone receptor (PR), and HER2 status in distant metastases has frequently been reported. The actual incidence of this phenomenon has been debated. Methods: We performed a meta-analysis including 39 studies assessing receptor conversion from primary breast tumors to paired distant breast cancer metastases. We noted the direction of change (positive to negative or vice versa) and performed subgroup analyses for different thresholds for positivity, the type of test used to assess HER2 receptor status, and metastasis location-specific differences (two-sided tests). Results: Overall, the incidence of receptor conversion varied largely between studies. For ERa, PR, and HER2, we found that random effects pooled positive to negative conversion percentages of 22.5% (95% confidence interval [CI] ¼ 16.4% to 30.0%), 49.4% (95% CI ¼ 40.5% to 58.2%), and 21.3% (95% CI ¼ 14.3% to 30.5%), respectively. Negative to positive conversion percentages were 21.5% (95% CI ¼ 18.1% to 25.5%), 15.9% (95% CI ¼ 11.3% to 22.0%), and 9.5% (95% CI ¼ 7.4% to 12.1%). Furthermore, ERa discordance was statistically significantly higher in the central nervous system and bone compared with liver metastases (20.8%, 95% CI ¼ 15.0% to 28.0%, and 29.3%, 95% CI ¼ 13.0% to 53.5%, vs 14.3%, 95% CI ¼ 11.3% to 18.1, P ¼ .008 and P < .001, respectively), and PR discordance was higher in bone (42.7%, 95% CI ¼ 35.1% to 50.6%, P < .001) and liver metastases (47.0%, 95% CI ¼ 41.0% to 53.0%, P < .001) compared with central nervous system metastases (23.3%, 95% CI ¼ 16.0% to 32.6%). Conclusions: Receptor conversion for ERa, PR, and HER2 occurs frequently in the course of disease progression in breast cancer. Large prospective studies assessing the impact of receptor conversion on treatment efficacy and survival are needed. Meanwhile, reassessing receptor status in metastases is strongly encouraged

Receptor conversion in distant breast cancer metastases : A Systematic Review and Meta-analysis

Background: In metastatic breast cancer, hormone and/or human epidermal growth factor receptor 2 (HER2)-targeted therapy decision-making is still largely based on tissue characteristics of the primary tumor. However, a change of estrogen receptor alpha (ERa), progesterone receptor (PR), and HER2 status in distant metastases has frequently been reported. The actual incidence of this phenomenon has been debated. Methods: We performed a meta-analysis including 39 studies assessing receptor conversion from primary breast tumors to paired distant breast cancer metastases. We noted the direction of change (positive to negative or vice versa) and performed subgroup analyses for different thresholds for positivity, the type of test used to assess HER2 receptor status, and metastasis location-specific differences (two-sided tests). Results: Overall, the incidence of receptor conversion varied largely between studies. For ERa, PR, and HER2, we found that random effects pooled positive to negative conversion percentages of 22.5% (95% confidence interval [CI] ¼ 16.4% to 30.0%), 49.4% (95% CI ¼ 40.5% to 58.2%), and 21.3% (95% CI ¼ 14.3% to 30.5%), respectively. Negative to positive conversion percentages were 21.5% (95% CI ¼ 18.1% to 25.5%), 15.9% (95% CI ¼ 11.3% to 22.0%), and 9.5% (95% CI ¼ 7.4% to 12.1%). Furthermore, ERa discordance was statistically significantly higher in the central nervous system and bone compared with liver metastases (20.8%, 95% CI ¼ 15.0% to 28.0%, and 29.3%, 95% CI ¼ 13.0% to 53.5%, vs 14.3%, 95% CI ¼ 11.3% to 18.1, P ¼ .008 and P < .001, respectively), and PR discordance was higher in bone (42.7%, 95% CI ¼ 35.1% to 50.6%, P < .001) and liver metastases (47.0%, 95% CI ¼ 41.0% to 53.0%, P < .001) compared with central nervous system metastases (23.3%, 95% CI ¼ 16.0% to 32.6%). Conclusions: Receptor conversion for ERa, PR, and HER2 occurs frequently in the course of disease progression in breast cancer. Large prospective studies assessing the impact of receptor conversion on treatment efficacy and survival are needed. Meanwhile, reassessing receptor status in metastases is strongly encouraged

Living in the twilight zone: a qualitative study on the experiences of patients with advanced cancer obtaining long-term response to immunotherapy or targeted therapy

Purpose: The introduction of immunotherapy and targeted therapy has drastically improved the life expectancy of patients with advanced cancer. Despite improved survival, obtaining long-term response can be highly distressing and comes with uncertainties that affect several life domains. The aim of this study is to gain a deeper understanding of long-term responders’ lived experiences with obtaining long-term response to immunotherapy or targeted therapy. Methods: We conducted an exploratory qualitative study using thematic data analysis. Semi-structured in-depth interviews were conducted with 17 patients with advanced melanoma or lung cancer who had a confirmed response to or long-term stable disease while on immunotherapy or targeted therapy. Results: Long-term responders are living in a twilight zone, where they neither feel like a patient, nor feel healthy. This impacts their self-image, interactions with their social environment, and feelings of uncertainty. Due to their uncertain life perspective, long-term responders are going back and forth between hope and despair, while they are longing for their ‘old’ life, several barriers, such as protective behavior of the social environment, force them to adjust to a life with cancer. Conclusion: Long-term responders are facing many challenges, such as searching for a renewed identity, dealing with ongoing uncertainty, and having to adapt to a new normal. This emphasizes the importance of providing this new patient group with tailored information and support. Implications for Cancer Survivors: Healthcare professionals can support patients by normalizing their feelings and providing space for varying emotions. Using patient-tailored scan frequencies could help temper fear of progression