Tag: General Medical Oncology & Hematology

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

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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 ICIs 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- Interferon-gamma, Neutrophil-to-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;28:535-544.

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

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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]

FDA Grants Tumor-Agnostic Accelerated Approval to RETEVMO®

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SUMMARY: The FDA on September 21, 2022, granted accelerated approval to Selpercatinib (RETEVMO®) for adult patients with locally advanced or metastatic solid tumors with a Rearranged during Transfection (RET) gene fusion that have progressed on or following prior systemic treatment, or who have no satisfactory alternative treatment options. The FDA on the same day also granted Regular approval to Selpercatinib for adult patients with locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC) with a Rearranged during Transfection (RET) gene fusion, as detected by an FDA-approved test. FDA also approved the Oncomine Dx Target (ODxT) Test as a companion diagnostic for Selpercatinib.

In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, NTRK, are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors.

RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene result in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, pancreas, breast, and several hematologic malignancies.

Selpercatinib is a highly selective and potent, oral anti-RET Tyrosine Kinase Inhibitor (TKI) designed to inhibit native RET signaling, as well as anticipated acquired resistance mechanisms. Selpercatinib selectively targets wild-type RET as well as various RET mutants and RET-containing fusion products. Additionally, Selpercatinib inhibits Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), VEGFR3, Fibroblast Growth Factor Receptor 1 (FGFR1), FGFR2, and FGFR3. This results in inhibition of cell growth of tumors that exhibit increased RET activity.

The LIBRETTO-001 is the largest open-label, multicenter, Phase I/II trial in patients with advanced solid tumors, including RET fusion-positive solid tumors, RET-mutant Medullary Thyroid Cancers, and other tumors with RET activation, treated with a RET inhibitor. To investigate the efficacy of Selpercatinib, the trial was conducted in 2 parts: Phase 1 (dose escalation) and Phase II (dose expansion). Patients with advanced cancer were eligible, if they have progressed on or were intolerant to available standard therapies, or no standard or available curative therapy existed, or in the opinion of the Investigator, they would be unlikely to tolerate or derive significant clinical benefit from appropriate standard of care therapy, or they declined standard therapy. A dose of 160 mg BID was the recommended Phase II dose. Up to about 850 patients with advanced solid tumors harboring a RET gene alteration in tumor and/or blood were enrolled in 6 different Phase II cohorts, based on tumor type, RET alteration and prior therapy. Identification of RET gene alterations were prospectively determined in local laboratories using either Next Generation Sequencing, Polymerase Chain Reaction, or Fluorescence In Situ Hybridization. The Phase II portion of the trial had a Primary endpoint of Objective Response Rate (ORR) by Blinded Independent Review Committee (BIRC) and Secondary endpoints of Duration of Response, CNS Objective Response Rate, Progression Free Survival (PFS) and safety.

RET Fusion-Positive Solid Tumors
This group included 41 patients and the most common cancers were pancreatic adenocarcinoma (27%), colorectal (24%), salivary (10%), and unknown primary (7%). Majority of the patients (90%) received 2 prior systemic therapies and 32% had received 3 or more. The median age of patients was 50 years, 54% were female, 68% were White, 24% were Asian, and 95% had metastatic disease. RET fusion-positive status was detected in 98% of patients using NGS and 2% using FISH.

The Objective Response Rate was 44%, with 5% Complete Response and 39% Partial Response. The median Duration of response was 24.5 months and 67% of patients had a Duration of Response of 6 months or more.

The NSCLC Cohort
Selpercatinib was previously granted accelerated approval in May 2020 for patients with metastatic RET fusion-positive NSCLC based on initial Overall Response Rate (ORR) and Duration of Response (DOR) among 144 patients enrolled in the LIBRETTO-001 trial. The conversion to regular and traditional FDA approval was based on data from an additional 172 patients and 18 months of additional follow up, to assess durability of response. Patients received Selpercatinib until disease progression or unacceptable toxicity and efficacy was evaluated in a total of 316 patients with locally advanced or metastatic RET fusion-positive NSCLC. The median age of patients was 61 years, 58% were female, 49% were White, 41% were Asian and 97% had metastatic disease. Previously treated patients received a median of two prior systemic therapies and 58% had received prior anti PD 1/PD-L1 therapy.

Among the 69 treatment-naïve patients, the ORR was 84%, with 6% Complete Response and 78% Partial Response. The median Duration of Response was 20.2 months and 50% of patients had a Duration of Response of 12 months or more. Among the 247 previously treated patients, the ORR was 61%, with 7% Complete Response and 54% Partial Response. The median Duration of Response was 28.6 months and 63% of patients had a Duration of Response of 12 months or more.

It is estimated that up to 50% of RET fusion-positive NSCLC patients can have brain metastases, and in the subset of patients with brain metastases (N=21), treatment with Selpercatinib demonstrated a CNS Objective Response Rate of 85%, and 38% of responders had an intracranial Duration of Response of 12 months or greater. The most common toxicities in patients were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.

LIBRETTO-001 is the largest trial ever reported in RET-altered cancer patients and represents an important milestone in the Precision Medicine arena. Selpercatinib is the first and only RET inhibitor to receive both tumor-agnostic accelerated approval and traditional approval in NSCLC, reinforcing its benefits across diverse tumor types.

Selpercatinib in patients with RET fusion–positive non–small-cell lung cancer: updated safety and efficacy from the registrational libretto-001 phase I/II trial.Published September 19, 2022. Drilon A, Subbiah V, Gautschi O, et al. J Clin Oncol. doi:10.1200/JCO.22.00393

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-locally-advanced-or-metastatic-ret-fusion-positive-solid-tumors

PREMMplus Hereditary Cancer Risk Assessment Tool May Identify People Likely to Benefit from Multigene Panel Testing

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SUMMARY: Hereditary factors play an important role in the risk of developing several cancers. Therefore, identification of a germline predisposition can have important implications for treatment decision making, risk-reducing interventions, cancer screening for early diagnosis, and germline testing and targeted surveillance of unaffected relatives. Previously published studies have been biased by estimating the prevalence of germline cancer susceptibility in patients with breast, prostate, and colorectal cancer from registry populations, genetic testing companies, and high-risk cancer clinics.

With the widespread adoption of Next Generation Sequencing (NGS), multiple genes can be tested simultaneously (MultiGene Panel Testing-MGPT), rather than sequential single-gene testing, making MultiGene Panel Testing cheaper, faster and more efficient. Further, single-test multigene multiplexing strategy analyzes numerous cancer susceptibility genes and frequently detects highly penetrant, clinically actionable Pathogenic Germline Variants (PGV) in individuals whose clinical histories fail to fulfill syndrome-specific testing criteria. This is clinically relevant, as it has become increasingly complex to determine which individuals warrant germline testing.

Several risk assessment models have been developed to provide probability of an individual carrying a germline mutation. However, these models only provide syndrome-specific risk assessment for Lynch Syndrome, Hereditary Breast and Ovarian Cancer syndrome (HBOC)), etc., and there is significant need for a risk assessment model tailored toward MultiGene Panel Testing.

The PREMM (PREdiction Model for gene Mutations) model has been rigorously tested, and is widely recognized and recommended by several professional societies, including the National Comprehensive Cancer Network (NCCN), the American College of Gastroenterology, and the U.S. Multi-Society Task Force on Colorectal Cancer. The PREMMplus model is a clinical prediction algorithm (tool) that estimates the cumulative probability of an individual carrying a germline mutation in 19 genes linked to cancer. Individuals are considered to be high risk if they have a risk score greater than 2.5%, and are eligible for genetic evaluation to determine if they indeed harbor germline mutations, and these individuals in turn could benefit from measures to prevent the cancer, or detect cancer early.

This aim of this study was to develop and validate PREMMplus clinical risk assessment tool (clinical prediction model) that could be used to identify individuals who are likely to have Pathogenic Germline Variant and should undergo MultiGene Panel Testing. PREMMplus was designed to identify individuals carrying Pathogenic Germline Variants in 19 cancer susceptibility genes broadly categorized by phenotypic overlap and/or relative penetrance, and they included 11 Category A genes (APC, BRCA1/2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53) and 8 Category B genes (ATM, BRIP1, CDKN2A, CHEK2, PALB2, PTEN, RAD51C, and RAD51D). Assessment of germline variant pathogenicity was based on the most recent classification made by the clinical laboratory, performing MultiGene Panel Testing. This clinical prediction model was designed to achieve both high sensitivity and Negative Predictive Value (NPV) across a diverse spectrum of syndromes, used clinical data only, did not require tumor tissue thus facilitating scalability, and was adaptable to allow for future expansion, as new genes became incorporated into routine MultiGene Panel Testing.

Clinical predictors for this model included demographics (sex, ancestry, and age at testing), as well as personal, and family history of specific cancers in first- and second-degree relatives. EIGHTEEN cancer types were selected for PREMMplus development, including both common malignancies such as breast cancer and colorectal cancer and uncommon malignancies such as sarcoma and adrenocortical carcinoma, associated with inherited risk. Individuals were excluded from analysis if a personal and family history of any of these 18 cancers were not available, and/or if age at MultiGene Panel Testing was missing. Individuals with 2 or more Pathogenic Germline Variants were excluded from the development cohort.

The performance of this clinical model was validated in nonoverlapping data sets of 8,691 and 14,849 individuals with prior MultiGene Panel Testing ascertained from clinic and laboratory-based settings, respectively.

PREMMplus demonstrated high sensitivity and high Negative Predictive Value for identifying individuals with Pathogenic Germline Variants in the 19 different cancer susceptibility genes. PREMMplus demonstrated a sensitivity of 93.9%, 91.7%, and 89.3% and Negative Predictive Value of 98.3%, 97.5%, and 97.8% for identifying Category A gene Pathogenic Germline Variants carriers, in the development and validation cohorts, respectively. PREMMplus demonstrated a sensitivity of 89.9%, 85.6%, and 84.2% and Negative Predictive Value of 95.0%, 93.5%, and 93.5% for identifying Category A/B gene Pathogenic Germline Variants carriers in the development and validation cohorts, respectively. Overall, 9.4%, 10.8%, and 9.2% of the development, clinic-based validation, and laboratory-based validation cohorts, respectively, harbored a Pathogenic Germline Variant in one of the 19 PREMMplus genes.

It was concluded that PREMMplus accurately identifies individuals with Pathogenic Germline Variants in a diverse spectrum of cancer susceptibility genes, with high sensitivity and Negative Predictive Value. PREMMplus represents a new evidence-based approach and can be used to identify individuals who should undergo MultiGene Panel Testing.

Development and Validation of the PREMMplus Model for Multigene Hereditary Cancer Risk Assessment. Yurgelun MB, Uno H, Furniss CS, et al. DOI: 10.1200/JCO.22.00120 Journal of Clinical Oncology

TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib)

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The FDA on June 22, 2022, granted accelerated approval to TAFINLAR® (Dabrafenib) in combination with MEKINIST® (Trametinib) for the treatment of adult and pediatric patients 6 years of age or older with unresectable or metastatic solid tumors with BRAF V600E mutation, who have progressed following prior treatment, and have no satisfactory alternative treatment options. TAFINLAR® and MEKINIST® are products of Novartis Pharmaceuticals Corporation.

 

VIJOICE® (Alpelisib)

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The FDA on April 5, 2022, granted accelerated approval to VIJOICE® for adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy. VIJOICE® is a product of Novartis Pharmaceuticals Corporation.

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

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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

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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]