Factors Associated with Mortality among Cancer Patients with COVID-19 Infection Compared with Those without Cancer

SUMMARY: The SARS-CoV-2 Coronavirus (COVID-19) induced pandemic first identified in December 2019 in Wuhan, China, has contributed to significant mortality and morbidity in the US, and the numbers of infected cases continue to increase worldwide. As of May 15, 2022, over ONE million individuals have died from COVID-19 in the USA. Majority of the patients present with treatment-resistant pyrexia and respiratory insufficiency, with some of these patients progressing to a more severe systemic disease and multiple organ dysfunction.

Patients with cancer are immunocompromised from either the underlying disease or therapy and are susceptible to infections with respiratory viruses. This is even more relevant with the emergence of the COVID-19 pandemic, and numerous studies have been conducted to understand the impact of infection with COVID-19 and outcomes in patients with cancer, infected with COVID-19, with discordant results. The understanding of possible risks, complications and outcomes of COVID-19 infection among cancer patients is important for patients and families, as well as health care systems.

The researchers conducted this study to assess the differences in clinical outcomes between cancer patients with SARS-CoV-2 infection and patients without cancer but with SARS-CoV-2 infection, and also to identify cancer patients at a high risk for poor outcomes. This systematic review and meta-analysis included 81 studies involving 61, 532 patients with cancer. Among 58 849 patients with available data, 52% were male median age ranged from 35- 74 years. Data was extracted from the PubMed, Web of Science, and Scopus databases until June 14, 2021. The main outcomes and measures were the difference in mortality between cancer patients with SARS-CoV-2 infection and control patients, as well as the difference in outcomes for various tumor types and cancer treatments. Majority of patients represented were from the US, UK, Italy, France and China.

In age and sex-matched analysis, the Relative Risk (RR) of mortality from COVID-19 among cancer patients compared to those without cancer was 1.69 (P<0.001). The risk of mortality among cancer patients versus those without cancer decreased with increasing age (Odds Ratio = 0.96; P=0.03). The researchers hypothesized that the reasons for this finding were likely associated with the type of cancer, the intensity of treatments, or behavioral factors such as increased social mixing among patients younger than 50 years, compared to that of an older population.

When mortality and Case Fatality Rate were analyzed by cancer type, the pooled Case Fatality Rate for patients with lung cancer and SARS-CoV-2 infection was 30% and the Relative Risk of mortality in those patients with lung cancer compared with other cancer types was significantly higher at 1.68 (P<0.001). This was followed by hematologic cancer with a pooled Case Fatality Rate for patients with hematologic cancer and SARS-CoV-2 infection of 32%, and the Relative Risk of mortality in patients with hematologic cancer and SARS-CoV-2 infection compared with those with solid malignant neoplasms was 1.42 (P<0.001). Breast cancer (RR, 0.51; P<0.001) and gynecological cancer (RR, 0.76; P=0 .009) were associated with a significantly lower risk of death.

When Case Fatality Rate was analyzed by treatment type, chemotherapy was associated with the highest overall pooled Case Fatality Rate of 30%, and endocrine therapy was associated with the lowest at 11%. Radiotherapy was associated with a Case Fatality Rate of 23%, Immunotherapy, as well as surgery within 3 months of a COVID-19 diagnosis in patients with cancer was associated with a Case Fatality Rate of 19% and targeted therapy was associated with a rate of 18%.

The authors from this analysis concluded that patients with cancer and SARS-CoV-2 infection had a higher risk of death, than patients without cancer. Risk factors associated with poor outcomes from COVID-19 included younger age, lung cancer, and hematologic malignancies.

Differences in Outcomes and Factors Associated With Mortality Among Patients With SARS-CoV-2 Infection and Cancer Compared With Those Without CancerA Systematic Review and Meta-analysis. Khoury E, Nevitt S, Madsen WR, et al. JAMA Netw Open. 2022;5(5):e2210880. doi:10.1001/jamanetworkopen.2022.10880

Expansion of Cancer Risk Profile beyond Breast and Ovarian Cancer for BRCA1 and BRCA2 Pathogenic Variants

SUMMARY: DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway.

BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in these genes predispose an individual to develop malignant tumors.

BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.

Pathogenic Variants (PVs) in BRCA1 and BRCA2 (BRCA1/2) are well known to be associated with increased lifetime risk for breast and ovarian cancer in women, and reliable risk estimates are also available and can be as high as 85% and 40% respectively. However, the association of BRCA1 and BRCA2 Pathogenic Variants with cancers other than female breast and ovarian cancers remain uncertain, and these associations have been based on studies with relatively small sample sizes, resulting in imprecise cancer risk estimates. It is therefore important that precise risk estimates are available, in order to optimize clinical management strategies and guidelines for cancer risk management in female and male BRCA1/2 carriers. The NCCN and other guidelines recommend breast and ovarian cancer screening for BRCA1/2 carriers, prostate cancer screening for BRCA2 carriers. Screening is also recommended for pancreatic cancer in BRCA1/2 carriers, but only in the presence of a positive family history of the disease.

The researchers conducted this study to evaluate the association of BRCA1 and BRCA2 pathogenic variants, with additional cancer types and their clinical characteristics associated with pathogenic variant carrier status. For this study, a large-scale registry based sequencing study was performed across 14 common cancer types in 63, 828 patients and 37, 086 controls, whose data were drawn from a Japanese nationwide multi-institutional hospital-based biobank, between 2003 and 2018. In the study group, the median age was 64 years and 42% were female, whereas the median age was 62 years and 47% were female in the control group. Germline pathogenic variants were identified in the BRCA1 and BRCA2 genes by a multiplex Polymerase Chain Reaction-based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls. Compared with the researchers previous publications for breast, colorectal, pancreatic, and prostate cancers, this study included 14,448 additional controls and 8247 additional cancer cases. These data thus provided a broad view of cancer risks associated with pathogenic variants in BRCA1 and BRCA2 genes.

Pathogenic variants in BRCA1 were significantly associated with increased risk for three other types of cancer types, Biliary tract (Odds Ratio–OR=17.4), Gastric (OR=5.2), and Pancreatic cancer (OR=12.6), in addition to female Breast (OR=16.1) and Ovarian cancer (OR=75.6). Pathogenic variants in BRCA2 increased risk for seven cancer types which included female Breast (OR=10.9), male Breast (OR=67.9), Gastric (OR=4.7), Ovarian (OR=11.3), Pancreatic (OR=10.7), Prostate (OR=4.0), and Esophageal cancer (OR=5.6). Further, Biliary tract, female Breast, Ovarian, and Prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives.

The results of this large study suggested that pathogenic variants in BRCA1 and/or BRCA2 are associated with increased risk of biliary tract, gastric, and esophageal cancers, higher than for European populations, granted that these cancers are known to have a higher incidence rate in East Asian countries. Conversely in this study, the cumulative risk of prostate cancer for BRCA2 carriers was lower than that estimated in the UK and Ireland, suggesting that the cumulative risk for each cancer type may be associated with the different incidence rate in each country.

The authors concluded that this study suggested that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types and is likely broader than that determined from previous analysis of largely European ancestry cohorts. It would therefore be useful to expand indications for genetic testing of individuals with family history of these cancer types.

Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants. Momozawa Y, Sasai R, Usui Y, et al. JAMA Oncol. 2022 Apr 14: e220476. doi: 10.1001/jamaoncol.2022.0476 [Epub ahead of print]

ORENCIA® (Abatacept)

The FDA on December 15, 2021, approved ORENCIA® (Abatacept) for the prophylaxis of acute Graft Versus Host Disease (aGVHD), in combination with a Calcineurin Inhibitor (CNI) and Methotrexate (MTX), in adults and pediatric patients 2 years of age and older undergoing Hematopoietic Stem Cell Transplantation (HSCT) from a matched or 1 allele-mismatched unrelated donor. This is the first drug approved to prevent aGVHD. The application included use of Real World Data (RWD) in the determination of clinical effectiveness. RWD is clinical data routinely collected from a variety of sources, including registry data, to generate Real World Evidence (RWE). ORENCIA® (Abatacept) is a product of Bristol-Myers Squibb Company.

JAKAFI® (Ruxolitinib)

The FDA on September 22, 2021 approved JAKAFI® (Ruxolitinib) for chronic Graft-Versus-Host Disease (cGVHD) after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older. JAKAFI® is a product of Incyte Corp.

Association of Gut Microbiome with Immune Checkpoint Inhibitor Response in Advanced Melanoma

SUMMARY: The American Cancer Society estimates that in 2022, there will be an estimated 1.92 million new cancer cases diagnosed and 609,360 cancer deaths in the United States. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Over 50% of patients treated with a combination of PD-1 and CTLA-4 inhibitors are alive after five years. Nonetheless, less than 50% of the patients respond to single-agent ICI and a higher response to targeting both PD-1 and CTLA-4 is associated with significant immune-related Adverse Events.

Biomarkers predicting responses to ICI’s include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL‐derived Interferon‐γ, Neutrophil‐to‐Lymphocyte ratio, and peripheral cytokines, have also been proposed as predictors of response. It has been postulated that concomitant medications during therapy with ICIs such as baseline steroid use as well as treatment with antibiotics may negate or lessen the efficacy of ICIs.

Preclinical studies have suggested that immune-based therapies for cancer may have a very complex interplay with the host’s microbiome and there may be a relationship between gut bacteria and immune response to cancer. The gut microbiome is unique in each individual, including identical twins. The crosstalk between microbiota in the gut and the immune system allows for the tolerance of commensal bacteria (normal microflora) and oral food antigens and at the same time enables the immune system to recognize and attack opportunistic bacteria. Immune Checkpoint Inhibitors strongly rely on the influence of the host’s microbiome, and the gut microbial diversity enhances mucosal immunity, dendritic cell function, and antigen presentation. Broad-spectrum antibiotics can potentially alter the bacterial composition and diversity of our gut microbiota, by killing the good bacteria. It has been postulated that this may negate the benefits of immunotherapy and influence treatment outcomes. It should be noted however that the relationship between gut bacteria and immune response is influenced by several factors and may be partially cancer type specific and it is unlikely that the same microbiome features can reflect the uniqueness of the genetic and immune characteristics of each tumor.

Even though the composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, there is a lack of consistency of results between the published studies, and there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. The Predicting Response to Immunotherapy for Melanona with Gut Microbiome and Metabolomics (PRIMM) studies are two separate prospective observational cohort studies that has been recruiting patients in the UK (PRIMM-UK) and the Netherlands (PRIMM-NL) since 2018. These cohorts of previously ICI-naive patients with advanced melanoma have provided extensive biosamples, including stool, serum and peripheral blood mononuclear cells, before and during ICI treatment, with detailed clinical and dietary data collected at regular intervals longitudinally.

The authors therefore performed a meta-analysis on existing publicly available datasets to produce the largest study to date. In order to study the role of the gut microbiome in ICI response, the researchers recruited ICI-naive patients with advanced cutaneous melanoma from the PRIMM cohorts, as well as three additional cohorts of ICI-naive patients with advanced cutaneous melanoma, originating from Barcelona, Leeds and Manchester (N = 165), and performed shotgun metagenomic sequencing on a total of 165 stool microbiome samples collected before initiating ICI treatment. Shotgun sequencing is a laboratory technique for determining the DNA sequence of an organism’s genome. This dataset was integrated with 147 metagenomic samples from smaller publicly available datasets. This methodology provided the largest assessment of the potential of the gut microbiome as a biomarker of response to ICI, in addition to allowing for investigation of specific microbial species or functions associated with response. Patient demographics including age, gender, BMI, previous non-immunotherapy treatments, previous drug therapies such as antibiotics, Proton Pump Inhibitors (PPIs) and steroids, as well as dietary patterns, were collected in these cohorts for the majority of patients, and were considered in the multivariate analysis.

The researchers used machine learning analysis to understand the association between gut microbiome and response to ICIs. This analysis confirmed the link between the microbiome and Overall Response Rates (ORRs), as well as Progression Free Survival (PFS) with ICIs. This analysis also revealed limited reproducibility of microbiome-based signatures across cohorts. A panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansiamuciniphila were associated with responders, but no single species could be regarded as a fully reliable biomarker across studies. Based on these findings from this large set of real-world cohorts, the authors noted that the relationship between human gut microbiome and response to ICIs is more complex than previously understood, and extends beyond the presence or absence of different microbial species in responders and nonresponders.

It was concluded that future studies should include large samples and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course. Until then, the authors recommend high-quality, diverse, whole-foods diet to optimize gut health, rather than consumption of commercial probiotics.

Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Lee KA, Thomas AM, Bolte LA, et al. Nat Med. 2022 Feb 28. doi: 10.1038/s41591-022-01695-5. Online ahead of print.

Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

SUMMARY: DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway.

BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in these genes predispose an individual to develop malignant tumors. It is well established that the presence of BRCA1 and BRCA2 mutations can significantly increase the lifetime risk for developing breast and ovarian cancer, as high as 85% and 40% respectively.

BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.

Pathogenic Variants (PVs) in BRCA1 and BRCA2 (BRCA1/2) are well known to be associated with increased lifetime risk for breast and ovarian cancer in women, and reliable risk estimates are also available and can be as high as 85% and 40% respectively. However, the association of BRCA1 and BRCA2 Pathogenic Variants with cancers other than female breast and ovarian cancers remain uncertain, and these associations have been based on studies with relatively small sample sizes, resulting in imprecise cancer risk estimates. It is therefore important that precise risk estimates are available, in order to optimize clinical management strategies and guidelines for cancer risk management in female and male BRCA1/2 carriers. The NCCN and other guidelines recommend breast and ovarian cancer screening for BRCA1/2 carriers, prostate cancer screening for BRCA2 carriers. Screening is also recommended for pancreatic cancer in BRCA1/2 carriers, but only in the presence of a positive family history of the disease.

The authors conducted this analysis to provide comprehensive and precise age-specific risk estimates of 22 cancers other than female breast and ovarian cancers associated with Pathogenic Variants in BRCA1 and BRCA2, for effective cancer risk management. The researchers used data from 3,184 BRCA1 families and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), to estimate age-specific Relative Risk (RR) and absolute risks for 22 first primary cancer types, after adjusting for family ascertainment. CIMBA was formed by a collaborative group of researchers working on genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers and provides sufficient sample sizes to allow large scale studies, in order to reliably evaluate the effects of genetic modifiers.

BRCA1 Pathogenic Variants were associated with significantly increased risk of male breast cancer (RR = 4.30; 4.3 times increased risk), pancreatic cancer (RR = 2.36), and stomach cancer (RR = 2.17). Although associations of BRCA1 Pathogenic Variants with colorectal and gallbladder cancers were observed, the results were not robust in the sensitivity analyses performed.

BRCA2 Pathogenic Variants were associated with increased risk of male breast cancer (RR = 44.0), stomach cancer (RR = 3.69), pancreatic cancer (RR = 3.34) and prostate cancer (RR = 2.22). Female carriers had a higher risk of stomach cancer than male carriers (RR = 6.89 versus 2.76; P=0.04).

The absolute/cumulative risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. In the present study, previously suggested associations of BRCA1 Pathogenic Variants with risks of other genitourinary cancers and increased risk of bone, brain, blood, gallbladder cancers and melanoma for BRCA2 Pathogenic Variants, were not replicated.

It was concluded from this analysis that in addition to female breast and ovarian cancers, BRCA1 and BRCA2 Pathogenic Variants are associated with increased risks of male breast cancer, pancreatic cancer, stomach cancer, and prostate cancer, the later only with BRCA2 Pathogenic Variants , but are not associated with the risks of other previously suggested cancers. These findings provide age-specific cancer risk estimates and will allow for improved cancer risk assessment of male and female BRCA1/2 carriers.

Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants. Li S, Silvestri V, Leslie G, et al. DOI: 10.1200/JCO.21.02112 Journal of Clinical Oncology – published online before print January 25, 2022.

Association of Age at Smoking Initiation and Cessation with Risk of Cancer Mortality

SUMMARY: According to the American Cancer Society, tobacco use is responsible for about 1 in 5 deaths in the United States and is the leading preventable cause of death in the US. Smoking (cigarettes, cigars, and pipes) is responsible for about 20% of all cancers and about 30% of all cancer deaths in the US. Approximately 80% of lung cancers, as well as about 80% of all lung cancer deaths, are due to smoking, and lung cancer is the leading cause of cancer death in both men and women. Smoking also increases the risk for cancers of the Oral cavity, Oropharynx, Larynx, Esophagus, Stomach, Liver, Pancreas, Colon/Rectum, Kidney, Bladder, Cervix, as well as Acute Myeloid Leukemia.

Previous published studies have shown that individuals who start smoking at a younger age have greater mortality risk than those who start smoking later in life, and quitting to smoke especially at younger ages substantially reduces that mortality risk. However, the relevance of age at smoking initiation and cessation to cancer mortality, in contemporary US populations, particularly across the life course, is not clear.

The authors in this prospective cohort study investigated the association between age at smoking initiation and cessation, and cancer mortality, at ages 25 to 79 years. Data for this study was used from a cohort of 410,231 participants in the US National Health Interview Survey from 1997 to 2014, linked to the National Death Index, and follow up was continued through December 31, 2015. The mean patient age was 48 years and 56% were female. Self-reported current daily smokers were categorized by age at smoking initiation (less than 10 yrs, 10-14 yrs, 15-17 yrs, 18-20 yrs, and 21 or more years). Ex-smokers were categorized by age at quitting (15-34 yrs, 35-44 yrs, 45-54 yrs, or 55-64 years). Current nondaily smokers (4% of cohort) and ex-smokers who quit at ages younger than 15 years or 65 years and older (1% of cohort) were excluded from the analysis. Cancer mortality rate ratios were adjusted for age at risk, sex, race and ethnicity, education, region and alcohol consumption.

There were 10,014 cancer deaths at ages 25 to 79 years during 3.7 million person-years of follow-up (mean=10 plus or minus 5 years). Compared with never smokers, the overall cancer mortality rate ratio associated with current smoking was 3.00, suggesting that current smoking was associated with three times the cancer mortality rate of never smoking.

For individuals who started smoking at age younger than 10 yrs, the cancer mortality rate ratio was 4.01, 3.57 for those ages 10-14 yrs, 3.15 for those ages 15-17 yrs, 2.86 for those ages 18-20 yrs and 2.44 for those ages 21 yrs and older. The researchers pointed out that if these excesses were interpreted as largely causal, smoking would account for 75% of cancer deaths among those starting before age 10 yrs and 59% among those starting at age 21 yrs and older. Those who quit smoking at ages 15-34 yrs, 35-44 yrs, 45-54 yrs, and 55-64 yrs avoided an estimated 100%, 89%, 78%, and 56% of the excess cancer mortality risk associated with continued smoking, respectively.

The authors concluded that in this contemporary US population, current smoking was associated with 3 times the cancer mortality rate of never smoking, and the researchers added that the findings from this study underscore that starting to smoke at any age is extremely hazardous. However, smokers who quit especially at younger ages can avoid most of the cancer mortality risk associated with continued smoking.

Association of Smoking Initiation and Cessation Across the Life Course and Cancer Mortality: Prospective Study of 410 000 US Adults. Thomson B, Emberson J, Lacey B, et al. JAMA Oncol. Published online October 21, 2021. doi:10.1001/jamaoncol.2021.4949