Association between antibiotic-immunotherapy exposure ratio and outcome in metastatic non small cell lung cancer

Galli, Giulia; Triulzi, Tiziana; Proto, Claudia; Signorelli, Diego; Imbimbo, Martina; Poggi, M.; Fucà, Giovanni; Ganzinelli, Monica; Vitali, Milena; Palmieri, Dario; Tessari, Anna; Braud, Filippo de; Garassino, Marina Chiara; Colombo, Mario P.; Russo, Giuseppe Lo

doi:10.1016/j.lungcan.2019.04.008

Cited by 61 publications

(52 citation statements)

References 39 publications

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“…The same trend was observed among 90 NSCLC patients treated with nivolumab, both in terms of progression-free survival and overall survival (53). In 47 NSCLC patients treated with immunotherapy and receiving antibiotics during the whole treatment period, a worse progression-free and overall survival was observed (54). Additionally, prolonged antibiotic use is strongly linked to lung cancer development (30).…”

Section: Effects Of the Microbiome On Cancer Therapysupporting

confidence: 55%

The Role of the Microbiome in Cancer and Therapy Efficacy: Focus on Lung Cancer

et al. 2020

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The microbiome is extremely important for human health; more recently its role in the context of cancer became clear. Microbial effects range from enhancing cancer immunity and cancer therapy efficacy, to promoting cancer progression and inhibiting treatment efficacy. These broad implications led researchers to investigate these specific interactions, as well as how modification of the microbiome can improve cancer survival and treatment efficacy. While these interactions are better established for cancers such as gastric cancer, they are far less understood in others. As nonsmall cell lung cancer (NSCLC) makes up the majority of lung cancer cases, and is among the top causes of cancer deaths worldwide, understanding the mechanisms by which the microbiome may impact progression and treatment is crucial to improve patient survival and treatment response. A literature review was conducted to reveal the crosslink between human microbiome and lung cancer. This includes immune priming, induction of pro-or anti-tumor response, and the local effects of intra-tumoral microbiota. Overall, this is a complex multifactorial relationship, and there are broad implications as to how this knowledge can improve cancer treatment. Solutions include manipulation of the microbiome using probiotics, bacterial vaccines and antibiotics. Bacteria biomarkers may also be used as a diagnostic tool. The microbiome, defined as the collection of genomes from all the microorganisms found in a particular environment, is an emerging and widely studied factor in human health. Its implications in cancer are manifold (1). Specific microorganisms that are found within a specific environment (i.e., the microbiota) induce anti-tumor immunity through immune priming (1, 2). Dysbiosis, genotoxins, and inflammatory responses to microbiota are associated with cancer development (1). Additionally, cancer treatment efficacy can be enhanced or inhibited by intra-tumoral and gut microbiota (3-5). This knowledge leads to many questions regarding the interactions between the microbiome, cancer and cancer therapies. Most importantly, how can a better understanding of these interactions lead to improvement of current treatment efficacy? Compared to the gastrointestinal (GI) tract, the microbiota of the lung and other organs are far less understood (4, 6). Lung cancer is the first cause of death among oncologic patients and the second most common cancer worldwide (7). Investigating microbial-cancer relationships will aid in a better understanding of the role of microbes in mechanisms underlying tumorigenesis behind this as well as other cancers and hopefully improve treatment efficacy (4). These factors are poorly understood in lung cancer (3, 8, 9). Therefore, this review aims 4807 This article is freely accessible online.

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Section: Effects Of the Microbiome On Cancer Therapysupporting

confidence: 55%

The Role of the Microbiome in Cancer and Therapy Efficacy: Focus on Lung Cancer

et al. 2020

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“…However, there were also a few studies that suggested no obvious association or impact. Interestingly, 2 prospective studies [23,24] and 1 retrospective study [25] provided seemingly different results (negative vs. no impact) when different timing of antibiotic exposure was put into consideration, suggesting that the timing and possibly the duration of antibiotics during ICI treatment are potentially important and will need further studies to clarify its impact..…”

Section: The Potential Impact Of Antibiotics On the Therapeutic Effecmentioning

confidence: 99%

“…) including 2 prospective[23,24] and 15 retrospective studies[9][10][11][25][26][27][28][29][30][31][32][33][34][35][36]. There were in total 2,593 participants with various solid tumors including lung cancer, melanoma, RCC, HCC, colorectal cancer, head and neck cancer, bladder cancer, gastric cancer, esophageal cancer, cervical cancer and others.…”

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confidence: 99%

Relating Gut Microbiome and Its Modulating Factors to Immunotherapy in Solid Tumors: A Systematic Review

Huang

Liu

et al. 2020

Preprint

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Background: Gut microbiome is proved to affect the activity of immunotherapy in certain tumors. However, little is known if there is universal impact on both the treatment response and adverse effects (AEs) of immune checkpoint inhibitors (ICIs) across multiple solid tumors, and whether such impact can be modulated by common gut microbiome modifiers, such as antibiotics and diet.Methods: A systematic search in PubMed followed by stringent manual review were performed to identify clinical cohort studies that evaluated the relevance of gut microbiome to ICIs (response and/or AEs, 12 studies), or association of antibiotics with ICIs (17 studies), or impact of diet on gut microbiome (16 studies). Only original studies published in English before April 1st, 2020 were used. Qualified studies identified in the reference were also included.Results: At the phylum level, patients who had enriched abundance in Firmicutes and Verrucomicrobia almost universally had better response from ICIs, whereas those who were enriched in Proteobacteria universally presented with unfavorable outcome. Mixed correlations were observed for Bacteroidetes in relating to treatment response. Regarding the AEs, Firmicutes correlated to higher incidence whereas Bacteroidetes were clearly associated with less occurrence. Interestingly, across various solid tumors, majority of the studies suggested a negative association of antibiotic use with clinical response from ICIs, especially within 1-2 month prior to the initiation of ICIs. Finally, we observed a significant correlation of plant-based diet in relating to the enrichment of “ICI-favoring” gut microbiome (P = 0.0476).Conclusions: Gut microbiome may serve as a novel modifiable biomarker for both the treatment response and AEs of ICIs across various solid tumors. Further study is needed to understand the underlying mechanism, minimize the negative impact of antibiotics on ICIs, and gain insight regarding the role of diet so that this important lifestyle factor can be harnessed to improve the therapeutic outcomes of cancer immunotherapy partly through its impact on gut microbiome.

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“…After early encouraging reports showing that the use of anthracyclines such as doxorubicin, epirubicin or idarubicin to treat various tumor types resulted in the potentiation of the patient's anti-tumor immunity [133], and data from other studies showed that antibiotic treatment had no deleterious effects on the response of non-small cell lung carcinomas (NSCLC) to treatment with the immune checkpoint inhibitor (ICI) nivolumab [134,135], results from preclinical chemo-immunotherapy protocols combining cyclophosphamide chemotherapy with adoptive T-cell (ACT) immunotherapy, using a mouse model of B-cell lymphoma, demonstrated that prophylactic use of broad-spectrum antibiotics reduced the efficacy of cyclophosphamide and impaired the therapeutic effects of ACT [136]. Since then, most studies have reported negative effects of antibiotic exposure leading to diminished levels of efficacy of ICIs in immunotherapy protocols for the treatment of a variety of tumors, including lung tumors/NSCLC [137][138][139][140][141][142][143][144], advanced or metastatic renal cell carcinoma [137,141,142,144], urothelial carcinoma [141], and melanoma [141,143,144]. In addition, more recently, it has been reported that antibiotic use had a negative impact on the response of patients with locally advanced head-and-neck tumors to treatment protocols involving chemotherapy or radiotherapy [145].…”

Section: Antibiotics and Cancer Therapy Outcomesmentioning

confidence: 99%

A Significant Question in Cancer Risk and Therapy: Are Antibiotics Positive or Negative Effectors? Current Answers and Possible Alternatives

Amadei

Notario

2020

Antibiotics

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Cancer is predominantly considered as an environmental disease caused by genetic or epigenetic alterations induced by exposure to extrinsic (e.g., carcinogens, pollutants, radiation) or intrinsic (e.g., metabolic, immune or genetic deficiencies). Over-exposure to antibiotics, which is favored by unregulated access as well as inappropriate prescriptions by physicians, is known to have led to serious health problems such as the rise of antibiotic resistance, in particular in poorly developed countries. In this review, the attention is focused on evaluating the effects of antibiotic exposure on cancer risk and on the outcome of cancer therapeutic protocols, either directly acting as extrinsic promoters, or indirectly, through interactions with the human gut microbiota. The preponderant evidence derived from information reported over the last 10 years confirms that antibiotic exposure tends to increase cancer risk and, unfortunately, that it reduces the efficacy of various forms of cancer therapy (e.g., chemo-, radio-, and immunotherapy alone or in combination). Alternatives to the current patterns of antibiotic use, such as introducing new antibiotics, bacteriophages or enzybiotics, and implementing dysbiosis-reducing microbiota modulatory strategies in oncology, are discussed. The information is in the end considered from the perspective of the most recent findings on the tumor-specific and intracellular location of the tumor microbiota, and of the most recent theories proposed to explain cancer etiology on the notion of regression of the eukaryotic cells and systems to stages characterized for a lack of coordination among their components of prokaryotic origin, which is promoted by injuries caused by environmental insults.

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Association between antibiotic-immunotherapy exposure ratio and outcome in metastatic non small cell lung cancer

Cited by 61 publications

References 39 publications

The Role of the Microbiome in Cancer and Therapy Efficacy: Focus on Lung Cancer

The Role of the Microbiome in Cancer and Therapy Efficacy: Focus on Lung Cancer

Relating Gut Microbiome and Its Modulating Factors to Immunotherapy in Solid Tumors: A Systematic Review

A Significant Question in Cancer Risk and Therapy: Are Antibiotics Positive or Negative Effectors? Current Answers and Possible Alternatives

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