Yu Fujiwara, MD, from Mount Sinai Beth Israel in New York City, and colleagues conducted a systematic review and meta-analysis to examine how adding an immune checkpoint blockade to perioperative therapy affects treatment-related adverse events. Data were included from 28 randomized controlled trials with 16,976 cancer patients.

The researchers found no significant association for addition of an immune checkpoint blockade with increased treatment-related deaths, and this finding was consistent across immune checkpoint blockade subtypes. Across 9864 patients treated with an immune checkpoint blockade, 40 fatal toxicities were identified, with pneumonitis the most common (15.0%); among 7112 patients who were not treated with an immune checkpoint blockade, 13 fatal toxicities were identified. The incidence rates of grade 3 to 4 treatment-related adverse events, adverse events leading to treatment discontinuation, and treatment-related adverse events of any grade were increased with the addition of an immune checkpoint blockade (odds ratios, 2.73, 3.67, and 2.60, respectively). Increased incidence rates of treatment-related deaths and grade 3 to 4 adverse events were seen in association with an immune checkpoint blockade vs placebo design primarily used as adjuvant therapy (odds ratios, 4.02 and 5.31, respectively), while incidence was not increased with the addition of an immune checkpoint blockade in the neoadjuvant setting.

“Our analysis points to a need for further research into risk factors and identification of appropriate biomarkers to predict both efficacy and toxicity associated with cancer immunotherapy,” Fujiwara said in a statement.

Several authors disclosed ties to the biopharmaceutical industry.

Abstract/Full Text (subscription or payment may be required)

Editorial (subscription or payment may be required)

Artificial intelligence (AI) chatbots can sometimes provide accurate information about cancers, but these tools have limitations, according to a pair of studies published in JAMA Oncology.^1,2

In the first study, researchers assessed chatbots’ responses to the top Internet searches related to 5 cancers.¹ The chatbots provided information that was generally of high quality but not always actionable, and it was written at a college reading level.

In the second study, researchers found that a chatbot’s responses to queries about cancer treatments did not always align with recommendations in National Comprehensive Cancer Network (NCCN) guidelines.²

Most-Searched Queries About Cancers

Alexander Pan, of SUNY Downstate Health Sciences University in Brooklyn, New York, and colleagues evaluated chatbots’ responses to the top 5 search queries for skin, colorectal, prostate, lung, and breast cancers.¹ All queries contained the terms “cancer symptoms” and “what is [specific cancer].”

The researchers tested 4 chatbots, ChatGPT, Perplexity, Chatsonic, and Bing AI. The team used the DISCERN validation tool to assess the quality of information the chatbots provided and the Patient Education Materials Assessment Tool (PEMAT) to analyze the understandability and actionability of responses. On a scale of 1-5 (DISCERN) or 0%-100% (PEMAT), higher scores on the validation tools indicated higher-quality responses.

The quality of the cancer information provided by the chatbots was high, with a median DISCERN score of 5 (range, 2-5). However, the information was of moderate understandability. The median PEMAT score was 66.7% (range, 33.3%-90.1%), which the researchers deemed “college reading level.” Furthermore, the chatbots often failed to provide actionable responses, with a median PEMAT score of 20.0% (range, 0%-40.0%).

“These limitations suggest that AI chatbots should be used supplementarily and not as a primary source for medical information,” the researchers concluded.

ChatGPT and Cancer Treatment Recommendations

Shan Chen, of Mass General Brigham in Boston, and colleagues evaluated whether ChatGPT responded to queries about cancer treatments with recommendations that were in line with NCCN guidelines.²

Because ChatGPT’s knowledge cutoff was September 2021, the researchers measured responses against the 2021 NCCN guidelines. Responses were assessed by board-certified oncologists. The researchers used 104 queries for breast, prostate, and lung cancer. The chatbot provided at least 1 treatment recommendation for 102 of the queries (98%). All of these responses included at least 1 NCCN-concordant recommendation, but 35 (34.3%) also included at least 1 non-concordant recommendation. Additionally, 13 of 104 chatbot responses (12.5%) were “hallucinated”, that is, they were not part of any recommended treatment for the specified cancer.

“The chatbot did not purport to be a medical device and need not be held to such standards,” the researchers noted. “However, patients will likely use such technologies in their self-education, which may affect shared decision-making and the patient-clinician relationship. Developers should have some responsibility to distribute technologies that do not cause harm, and patients and clinicians need to be aware of these technologies’ limitations.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original references for a full list of disclosures.

Avzivi is a vascular endothelial growth factor inhibitor indicated for the treatment of:

• Metastatic colorectal cancer, in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment.
• Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab product-containing regimen.
• Unresectable, locally advanced, recurrent or metastatic nonsquamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first-line treatment.
• Recurrent glioblastoma in adults.
• Metastatic renal cell carcinoma in combination with interferon alfa.
• Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.
• Epithelial ovarian, fallopian tube, or primary peritoneal cancer, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens.

The approval was based on a comprehensive data package that included a pharmacokinetic study (ClinicalTrials.gov Identifier: NCT05865574) in healthy individuals, as well as a phase 3 comparative study (ClinicalTrials.gov Identifier: NCT03329911) in patients with advanced nonsquamous non-small cell lung cancer.

“The global phase 3 clinical trial has confirmed that Avzivi is highly similar to Avastin in terms of efficacy, safety and immunogenicity,” said professor Li Zhang, leading investigator for global phase 3 study of Avzivi. “The approval of Avzivi by the FDA will provide lung and colorectal cancer patients a new cost-effective treatment option.”

Breakthroughs in targeted therapy and immunotherapy are partly responsible for the recent decline in cancer deaths seen in the United States, according to the AACR Cancer Progress Report 2023.¹

The overall rate of cancer death in the US fell by 33% between 1991 and 2020, which translates to 3.8 million lives saved, according to the report. Death rates have decreased for lung cancer, colorectal cancer, prostate cancer, female breast cancer, and melanoma.

“These gains have really reflected a whole variety of different advances, but mostly this has been about efforts in basic science,” AACR President Philip D. Greenberg, MD, of Fred Hutchinson Cancer Research Center in Seattle, said during a presentation about the AACR report.

Dr Greenberg noted that initiatives such as the Human Genome Project and The Cancer Genome Atlas have enabled the creation of targeted therapies, which are “increasingly precise and decreasingly toxic.”

Immunotherapy breakthroughs have also reduced the toxicity of treatments, leading to improved quality of life for patients. “Precision oncology, personalized medicine; it’s about creating drugs and using them to very selectively target the disease and not injure the person,” Dr Greenberg summarized.

The AACR report highlighted several targeted therapies with unique mechanisms of action that have been approved by the US Food and Drug Administration (FDA) since the early 2000s, including gefitinib in 2003, crizotinib in 2011, and sotorasib in 2021.

All of these therapies were approved to treat lung cancer, and these approvals coincided with declining lung cancer deaths. The decrease in lung cancer deaths per year grew from 0.9% between 1995 and 2005 to nearly 5% between 2014 and 2020.

The report also highlighted more recent FDA approvals. Between August 1, 2022, and July 31, 2023, the FDA approved 14 new cancer therapies and expanded the approved use of 12 therapies to encompass new cancers. The therapies include a range of cell-signaling inhibitors, antibody-drug conjugates, bispecific antibodies, and immune checkpoint inhibitors.

“A decade ago, there was 1 single immune checkpoint inhibitor,” Dr Greenberg pointed out. “Now . . . 11 checkpoint inhibitors have now been approved by the FDA up through 2023. And rather than using it to treat the single disease that it was approved for a decade ago, we now use it to treat 20 diseases.”

Two new imaging agents — pafolacianine and flotufolastat fluorine-18 —were also approved by the FDA between August 1, 2022, and July 31, 2023.

Ongoing Challenges

“Of course, despite all this progress, there’s a whole lot of work that needs to be done,” Dr Greenberg said. “There are still, even now, structural barriers for lots of people. There’s clearly disproportionate medical care being delivered to medically underserved populations. This includes, of course, racial and ethnic minorities, but it also includes the rural populations, which is not commonly appreciated, but rural populations participate very minimally in cancer trials.”

“Similarly, although precision medicine has really improved outcomes, we need ways of expanding that so that it includes more diseases,” Dr Greenberg added. “Pancreatic cancer, for example, and glioblastoma still have horrible 5-year relative survival rates, and so we need new advances.”

To address some of these challenges, the AACR has launched a new initiative known as the AACR Cancer Centers Alliance.²  The initiative aims to encourage collaboration among US cancer centers and “accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources . . ., and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.”²

Dr Greenberg suggested that the future of cancer research is bright. “I really enthusiastically look forward to what can happen,” he said. “I think there’s no reason not to be optimistic. . . . We’re in this time of unparalleled opportunities.”

Disclosures: Dr Greenberg has relationships with Affini-T, Rapt Therapeutics, Elpiscience, Fibrogen, Immunoscape, Metagenomi, Earli, Catalio, and Nextech. No disclosures were provided in relation to the AACR Cancer Progress Report 2023. Some authors of the Cancer Discovery article declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the article for a full list of disclosures.

Cancer patients were more likely to die from the BA.1 and BA.2 omicron variants of SARS-CoV-2 than from wild-type SARS-CoV-2, according to research published in JAMA Oncology.^1,2

The study showed that, among US cancer patients, COVID-19 deaths were more likely during the initial omicron wave when the BA.1 and BA.2 variants were in circulation (December 2021 to February 2022) than when wild-type SARS-CoV-2 was circulating (December 2020 to February 2021).

According to data from the US Centers for Disease Control and Prevention, there were 54,692 COVID-19 deaths among patients with cancer and 1,008,510 COVID-19 deaths in the general population from March 1, 2020, through May 31, 2022.

This study included 34,350 patients with cancer and 628,156 individuals from the general population who died from COVID-19 when wild-type SARS-CoV-2 was in circulation (December 2020-February 2021), the delta variant was in circulation (July 2021-November 2021), or the BA.1 and BA.2 omicron variants were in circulation (December 2021-February 2022).

The highest number of COVID-19-related deaths among patients with cancer occurred during the 2021-2022 omicron wave. At the peak of this wave, in January 2022, there were 18% more deaths than during the peak of the wild-type period, which occurred during January 2021.

This trend was maintained when patients were stratified by age group. The number of deaths per month among patients with cancer younger than 50 years of age was 64% higher during the 2021 to 2022 omicron wave than during the wild-type wave. The number was 62% higher among patients aged 50 to 59 years, 31% higher for those aged 60 to 69 years, and 16% higher for those aged 70 to 79 years.

When the researchers looked at individual cancer types, they found that COVID-19 deaths were more likely during the 2021-2022 omicron wave for most cancer types. The exceptions were brain cancer (mortality ratio [MR], 0.77; 95% CI, 0.65-0.90), thyroid cancer (MR, 0.76; 95% CI, 0.54-0.99), and bladder cancer (MR, 0.58; 95% CI, 0.52-0.65).

Patients with lymphoma had the greatest increase in deaths from the wild-type wave to the 2021 to 2022 omicron wave, at 38% (mortality ratio [MR], 1.38; 95% CI, 1.31-1.45).

In the general population, the highest number of COVID-19 deaths per month occurred when wild-type SARS-CoV-2 was prevalent. At the peak of the initial omicron wave in January 2022, there were 21% fewer deaths in the general US population than at the peak of the wild-type period in January 2021 (MR, 0.69; 95% CI, 0.69-0.70).

“[W]hile the general US population experienced a large reduction in COVID-19 mortality during the winter Omicron period, patients with cancer experienced the highest COVID-19 mortality during the winter Omicron period, likely due to increased SARS-CoV-2 exposure during this period combined with the reduced effectiveness of COVID-19 vaccines and increased risk of COVID-19 mortality in this population,” the researchers wrote. “With future COVID-19 waves imminent, strategies to protect those at highest risk should remain a high priority, even during future pandemic waves with less virulent SARS-CoV-2 variants.”

Disclosures: One of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

References

1. Potter AL, Vaddaraju V, Venkateswaran S, et al. Deaths due to COVID-19 in patients with cancer during different waves of the pandemic in the US. JAMA Oncol. Published online August 31, 2023. doi: 10.1001/jamaoncol.2023.3066

2. SARS-CoV-2 sequences by variant, United States, Jan 3, 2022. Our World in Data. Updated August 22, 2023. Accessed September 1, 2023.

Chemotherapy-Induced Nausea and Vomiting Prophylaxis

The cisplatin shortage that has affected cancer centers and patients across the US is nearly resolved, according to a statement from the Biden Administration.¹

The White House reported last week that the cisplatin supply has been restored to almost 100% of pre-shortage levels.

According to the US Food and Drug Administration’s (FDA) drug shortage database, 3 companies had cisplatin available on allocation as of September 18.² Additional supplies of cisplatin are expected to be released this month and next month.

The shortage of cisplatin has occurred alongside prolonged shortages of several other cancer drugs, including methotrexate and carboplatin.³ In June, the National Comprehensive Cancer Network (NCCN) published survey results reporting that cisplatin was in short supply at 70% of included cancer centers, and carboplatin was in short supply at 93%.⁴

The FDA has worked to alleviate these shortages over the past several months.¹ In June, the FDA announced that it would work with Chinese drugmaker Qilu Pharmaceutical and Canadian pharmaceutical company Apotex to temporarily import cisplatin.⁵ According to the FDA, distribution of this product has been completed.²

The FDA also worked with various drug manufacturers to increase production of cisplatin, carboplatin, and methotrexate.¹ According to the FDA database, several companies have methotrexate and carboplatin available now, and additional supplies of both drugs are expected this month and next month.²

“The Administration will continue to work through the FDA, the Department of Health and Human Services, and other agencies to address and prevent drug shortages and mitigate impacts to people facing a cancer diagnosis,” the White House said in its statement.¹

This is despite the fact that cancer survivors are more likely to be vaccinated against COVID-19 and just as likely as the general population to be infected with SARS-CoV-2. These findings were published in the Journal of the National Cancer Institute.

For this study, researchers evaluated data from the National Health Interview Survey in 2021 and 2022. The cohort from 2021 included 3428 cancer survivors and 26,023 control individuals without a cancer history. The cohort from 2022 included 3218 cancer survivors and 24,393 control individuals.

The cancer survivors were more likely than control individuals to have received 2 or more COVID-19 vaccines in 2021 (66.6% and 62.3%, respectively; P =.003) and 2022 (77.0% and 72.4%, respectively; P <.001).

However, cancer survivors were just as likely as control individuals to report having COVID-19 in 2021 (14.1% and 14.2%, respectively; P =.93) and 2022 (39.9% and 39.3%, respectively; P =.55).

Cancer survivors were more likely than control individuals to report moderate to severe COVID-19 symptoms in 2021 (62.5% and 54.2%, respectively; P =.02). In 2022, there was a trend toward more moderate and severe COVID-19 among cancer survivors, but the difference between cancer survivors and control individuals was not statistically significant (54.5% and 51.3%, respectively; P =.13).

However, the data from 2022 showed that cancer survivors were more likely than control individuals to have symptoms of long COVID (20.6% and 17.3%, respectively; P =.04). There were no data on long COVID from 2021.

“With the continuing high infectious rate and seasonal resurgences of COVID-19 infections and ongoing recommendations for vaccination, especially for vulnerable populations, monitoring the impact of COVID-19 infection and the effectiveness of prevention and control strategies continue to be a public health priority,” the researchers wrote. “Our findings suggest the need for tailored efforts to prevent and control COVID-19 infection for cancer survivors.”

Drug-Induced Photosensitivity

Jubbonti is approved to treat postmenopausal women with osteoporosis at high risk for fracture, to increase bone mass in men with osteoporosis at high risk for fracture, to treat glucocorticoid-induced osteoporosis in men and women at high risk for fracture, to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, and to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. The Jubbonti approval also includes a Risk Evaluation and Mitigation Strategy program designed to inform prescribers of the risk of severe hypocalcemia in patients with advanced kidney disease. 

Wyost is indicated to prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors, to treat adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity, and to treat hypercalcemia of malignancy refractory to bisphosphonate therapy.

For this approval, the FDA reviewed a comprehensive clinical data package, which included data from the phase 3 ROSALIA trial (ClinicalTrials.gov Identifier: NCT03974100). The study compared denosumab-bbdz to the reference product (Prolia) in 527 postmenopausal women with osteoporosis. Study participants were randomly assigned to receive the biosimilar or the reference product for up to 78 weeks of treatment. Findings showed the biosimilar denosumab was comparable to the reference product with regard to pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity.

The availability of Jubbonti and Wyost is still unclear as ongoing patent litigation precludes Sandoz from launching the products at this time.

The Food and Drug Administration (FDA) has approved Ogsiveo (nirogacestat) for adult patients with progressing desmoid tumors who require systematic treatment.

Desmoid tumors, also known as aggressive fibromatosis or desmoid-type fibromatosis, are rare, generally nonmalignant, soft tissue tumors that are abnormal growths of connective tissue. Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor that works by blocking proteolytic activation of Notch receptors, which when dysregulated, contribute to tumor growth.

“Desmoid tumors are rare tumors that can lead to severe pain and disability,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Today’s approval will offer the first approved treatment option for patients beyond surgery and radiation.”

The approval was based on data from the double-blind, placebo-controlled phase 3 DeFi trial (ClinicalTrials.gov Identifier: NCT03785964), which included 142 adult patients with progressing desmoid tumors not amenable to surgery. Patients were randomly assigned to receive either nirogacestat 150mg orally twice daily (n=70) or placebo (n=72). The primary endpoint was progression free survival.

Findings demonstrated that treatment with nirogacestat significantly reduced the risk of disease progression by 71% compared with placebo (hazard ratio, 0.29 [95% CI, 0.15-0.55]; P <.001). The median Kaplan-Meier estimate of PFS was not reached in the nirogacestat arm and was 15.1 months in the placebo arm. 

Confirmed objective response rate was reported to be 41% with nirogacestat vs 8% with placebo (P <.001); complete response rate was 7% in the nirogacestat arm and 0% in the placebo arm. Median time to first response was 5.6 months with nirogacestat and 11.1 months with placebo.

Treatment with nirogacestat also met key secondary endpoints of patient-reported outcomes, including reduced pain (P <.001) and other desmoid tumor-specific symptoms (P <.001), improved physical/role functioning (P <.001) and overall health-related quality of life (P ≤.01).

The most common adverse reactions reported with Ogsiveo were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea. Laboratory abnormalities included decreased phosphate, increased urine glucose, increased urine protein, increased AST, increased ALT, and decreased potassium. 

“As a treating physician, it was encouraging to see in the DeFi trial that Ogsiveo achieved statistically significant and clinically meaningful improvements across the primary and all key secondary endpoints, while also having a manageable safety profile,” said Mrinal M. Gounder, MD, sarcoma medical oncologist at Memorial Sloan Kettering Cancer Center in New York City and an investigator in the phase 3 DeFi trial. “This approval represents an important therapeutic advance for patients.”

Ogsiveo is supplied as a 50mg tablet. The recommended dosage is 150mg administered orally twice daily until disease progression or unacceptable toxicity. Each 150mg dose consists of three 50mg tablets.

According to SpringWorks, Ogsiveo will be available to order through a specialty pharmacy and specialty distributor network within 5 to 10 business days. The Company is also providing its comprehensive patient support program, SpringWorks CareConnections, to eligible patients. 

The Food and Drug Administration (FDA) has extended the review period of the New Drug Application (NDA) for nirogacestat, an investigational treatment for adults with desmoid tumors.

The new Prescription Drug User Fee Act target date is November 27, 2023. The FDA extended the action date by 3 months to allow more time to review additional data from clinical trials. According to SpringWorks Therapeutics, the FDA considered this information to be a major amendment to the application.

Desmoid tumors, also known as aggressive fibromatosis or desmoid-type fibromatosis, are rare, generally nonmalignant, soft tissue tumors that are abnormal growths of connective tissue. Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor that works by blocking proteolytic activation of Notch receptors. 

The NDA for nirogacestat was accepted for Priority Review in February 2023 based on data from the phase 3 DeFi trial (ClinicalTrials.gov Identifier: NCT03785964). Findings demonstrated that treatment with nirogacestat significantly reduced the risk of disease progression by 71% compared with placebo.

“We are confident that the comprehensive data from our phase 3 DeFi trial demonstrate the transformative benefits that nirogacestat can bring to people with desmoid tumors, who currently do not have an approved therapy,” said Saqib Islam, CEO of SpringWorks. “We remain committed to bringing this much needed therapy to patients and believe that our operational and manufacturing readiness positions us well to rapidly serve the desmoid tumor community following an approval. We look forward to continuing to work closely with the FDA as they complete their review of the nirogacestat NDA.”

For this study, the researchers used data from the cancer program of the 100,000 Genomes Project. They performed whole-genome sequencing (WGS) on 13,880 tumor samples encompassing 33 cancer types, as well as 13,616 matched normal samples.

The most common tumor types included were invasive breast carcinoma (n=2925), colon adenocarcinoma (n=1948), sarcoma (n=1617), and clear cell renal cell carcinoma (n=1163).

Clinically relevant genetic variants, as indicated by their presence in the National Genomic Test Directory for Cancer (NGTDC), were seen in more than 50% of tumor samples for glioblastoma, low-grade glioma, cutaneous melanoma, head and neck squamous cell carcinoma, colon and rectal adenocarcinoma, and lung adenocarcinoma.

Clinically relevant variants were also found in 20% to 49% of invasive breast carcinomas, high-grade serous ovarian carcinomas, mesotheliomas, sarcomas, endometrial cancers, urothelial carcinomas, and squamous cell lung carcinomas. Less than 20% of pancreatic, prostate, esophageal, and stomach adenocarcinomas had mutations in genes listed in the NGTDC.

Somatic and Germline Variants

TP53 was the most frequently mutated gene, with mutations found in 5411 samples (39.0%). TP53 was mutated in more than 70% of cases of uterine corpus endometrial serous carcinoma, high-grade serous ovarian carcinoma, lung squamous cell carcinoma, rectal adenocarcinoma, esophageal adenocarcinoma, and esophageal squamous cell carcinoma.

The second most frequently mutated gene was PIK3CA, with mutations found in 2750 patients (19.8%). Mutations in this gene occurred most often in uterine corpus endometrial carcinoma (53.5%), ovarian endometrioid adenocarcinoma (49.0%), invasive breast carcinoma (42.2%), uterine corpus endometrial serous carcinoma (38.1%), and colon adenocarcinoma (26.5%).

The highest prevalence of actionable germline variants was seen in high-grade serous ovarian carcinoma, in which 13% of patients had variants in BRCA1 and BRCA2. Patients with these variants tended to have a younger age at diagnosis.

Similarly, patients with germline variants in mismatch-repair genes had earlier age of onset for colon cancer. Earlier age of onset was also seen in patients with high-grade serous ovarian carcinoma or invasive breast carcinoma who had germline mutations in homologous recombination repair genes, and in clear cell renal cell carcinoma patients with germline variants in the VHL gene.

Biomarkers and Mutational Signatures

The researchers noted significant variations in tumor mutational burden (TMB) across cancer types, with cutaneous melanoma and lung adenocarcinoma having the highest average TMB.

In addition, certain mutational signatures were associated with certain cancer types. APOBEC signatures 2 and 13 were associated with invasive breast carcinoma, head and neck squamous cell carcinoma, urothelial carcinoma, and lung adenocarcinoma. Smoking signatures 4 and 92 were associated with lung cancers, and ultraviolet signatures 7a-d were associated with cutaneous melanoma.

The researchers also found the highest prevalence of homologous recombination deficiency (HRD) in high-grade serous ovarian carcinoma (40%), but HRD was seen in other tumors as well.

Clinical Outcomes

By linking the WGS data with longitudinal clinical data, the researchers evaluated treatment outcomes, stratified according to pangenomic markers. In patients who received platinum therapy (n=189), for example, the presence of HRD was associated with a lower risk of death (hazard ratio [HR], 0.37; 95% CI, 0.23-0.61; P <.001), particularly in patients with invasive breast carcinomas or high-grade serous ovarian carcinomas.

In patients with cutaneous melanoma, those with low TMB had significantly shorter overall survival (OS) than those with high TMB (HR, 2.34; 95% CI, 1.14-4.80; P =.015). A similar difference was not seen in lung cancer (P =.72).

“This may indicate that the level of TMB is relevant in prognosis and supports the need for further refining of pangenomic biomarkers as both prognostic and predictive for immunotherapy response, as highlighted in previous studies,” the researchers noted. The researchers also evaluated OS in all 33 cancer types, stratified according to the presence or absence of mutations in 40 NGTDC-indicated genes. This analysis revealed 15 genes that affect OS.

The gene that most affected OS was CDKN2A (HR, 2.3; 95% CI, 2.0-2.6; P <1×10⁻¹⁰), “which corresponds to its association with high-grade disease and poor prognosis in some cancer subtypes, such as glioma and soft-tissue sarcoma,” according to the researchers.

Other results were as expected, with the presence of KRAS mutations in colorectal cancer and KRAS and TP53 mutations in non-small cell lung cancer indicating poor prognosis, and PIK3CA mutations associated with favorable outcomes. The researchers predicted that additional prognostic implications of WGS will be established as this dataset grows and is integrated with data from patients’ life course as well as data from other sequencing modalities, such as cell-free DNA and single-cell sequencing.

“Our findings demonstrate the utility of linking genomic and real-world clinical data to enable survival analysis to identify cancer genes that affect prognosis and advance our understanding of how cancer genomics impacts patient outcomes,” the researchers concluded.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.