! I’m your host today, Courtney Flaherty.

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, we had the pleasure of speaking with Amin Nassar, MD, and Elias Bou Farhat, MD, regarding their evaluation of the feasibility and accuracy of using next-generation sequencing (NGS) mutation signature for assessing and identifying mismatch repair–deficient (dMMR) tumors compared with standard MMR immunohistochemistry (IHC) testing. Dr Nassar is a hematology/oncology fellow at Yale University in New Haven, Connecticut. Dr Bou Farhat is a postdoctoral research fellow in the Department of Medicine at Brigham and Women’s Hospital in Boston, Massachusetts.

The retrospective study found that an additional 6.9% of patients with dMMR colorectal or endometrial cancer that were missed by IHC but detected by NGS-based mutation signature (NGS/IHC discordant) experienced comparable clinical outcomes to those of patients identified as dMMR by both IHC and mutation signature (NGS/IHC concordant) across tumor types. Moreover, improvements in overall survival (OS) and time to treatment failure were observed in the discordant group vs those with concordant MMR-proficient (pMMR) tumors. The median OS was also prolonged in patients with discordant CRC or endometrial tumors who received immune checkpoint inhibitors vs those who were not previously exposed to checkpoint inhibitors and received other systemic therapies.

Ultimately, investigators concluded that tumor-only NGS demonstrated high sensitivity for detecting MMR signature analysis in patients with CRC or endometrial cancer and could be employed as a complementary test alongside IHC to improve the identification of patients who may benefit from immunotherapy.

In our exclusive interview, Drs Nassar and Bou Farhat explained how tumor-only NGS could address the limitations of IHC testing for MMR mutation signatures across several tumor types, discussed primary findings and concordance rates from the study, and proposed revisiting guideline recommendation on diagnostic testing to reduce the impact of misdiagnosis of MMR status on treatment outcomes.

That’s all we have for today! Thank you for listening to this episode of 

. Check back on Mondays and Thursdays for exclusive interviews with leading experts in the oncology field.

For more updates in oncology, be sure to visit www.OncLive.com and sign up for our e-newsletters.

® is also on social media. On Twitter, follow us at @OncLive. On Facebook, like us at OncLive, and follow our 

, please consider subscribing to our podcast on Apple Podcasts, Spotify, Google Podcasts, Amazon Music, and many of your other favorite podcast platforms,* so you get a notification every time a new episode is posted. While you are there, please take a moment to rate us!

 is available on: Apple Podcasts, Google Podcasts, Spotify, Amazon Music, Audacy, CastBox, Deezer, iHeart, JioSaavn, Listen Notes, Player FM, Podcast Addict, Podchaser, RadioPublic, and TuneIn.

Podcasts

Drs Nassar and Bou Farhat explain how tumor-only NGS could address the limitations of IHC testing for MMR mutation signatures across several tumor types. 

Bou Farhat and Nassar on the Use of NGS Mutation Signature vs IHC for Identifying dMMR Tumors

Amin Nassar, MD, discusses the investigation of NGS plus standard IHC to detect dMMR status in patients with colorectal cancer or endometrial cancer.  

Amin Nassar, MD, clinical fellow, hematology/oncology, Yale University, Yale School of Medicine, 

discusses the investigation of next-generation sequencing

 (NGS) alongside standard immunohistochemistry (IHC) to detect mismatch repair (MMR) deficiency (dMMR) in patients with colorectal cancer (CRC) or endometrial cancer.

The rationale behind evaluating the concordance between determining MMR status by IHC and NGS stemmed from the need to enhance the detection of dMMR in patients with CRC and endometrial cancer. Although standard IHC is currently the preferred dMMR detection method due to its accessibility and prompt turnaround time, its reliance on antigen-antibody binding may overlook cases where a mutation in the epitope preserves antigen expression but disrupts functionality, leading to misclassification of tumors as MMR proficient, Nassar begins. Recognizing that some patients with dMMR disease might be missed by IHC, the aim of the investigation was to quantify this patient subset and determine whether dMMR status could be identified using NGS, potentially identifying additional patients who might benefit from immunotherapy despite being overlooked by IHC, he reports.

Compared with IHC, which solely focuses on the antigen-antibody binding site, NGS offers a broader detection approach by genotyping multiple regions in the genome, he expands. Investigators hypothesized that NGS would offer greater sensitivity and accuracy compared with IHC, although this assertion lacked empirical evidence, Nassar explains. Despite ongoing discussions among various organizations, the absence of data demonstrating the efficacy of NGS in identifying patients who could benefit from immunotherapy has hindered its incorporation into clinical guidelines, he elucidates.

A prior study highlighted the consequences of misdiagnosis in MMR status and microsatellite instability with immune checkpoint inhibitors, Nassar continues, adding that although immune checkpoint inhibition is highly effective in dMMR patients, a subset of patients with dMMR disease does not derive benefit from this treatment approach. Investigation revealed that many of these patients were misdiagnosed as dMMR, raising concerns about potential false positives with IHC, he notes. Hence, exploring NGS as a method to minimize false positives and false negatives becomes crucial for improving patient outcomes and optimizing immunotherapy efficacy, Nassar concludes.

Videos

Amin Nassar, MD, discusses the investigation of NGS plus standard IHC to detect dMMR status in patients with colorectal cancer or endometrial cancer.

Dr Nassar on MMR Determination by IHC and NGS in CRC and Endometrial Cancer

My research in population genetics integrates genetics and large-scale electronic health record data to identify meaningful biomarkers of treatment consequences and develop algorithmic models to support clinical decision-making. Additionally, it emphasizes that genomic inequities aggravate existing health disparities and bias genetic discoveries toward more represented populations. As such, I focus on the identification of genomic biomarkers across ancestral populations with cancer. This has culminated in several high-impact publications, which include but are not limited to as follows: 

The identification of the distribution of 

 across cancer types and by sex and race. As 

 G12C mutations are important targetable drivers, this was the first comprehensive description of the prevalence of this mutation across different populations. 

Germline variant contamination has varying impacts on tumor mutational burden (TMB). 

Pembrolizumab (Keytruda) is an FDA-approved immune checkpoint inhibitor (ICI) for patients with high TMB (≥ 10 variants/megabase) based on the tumor-only sequencing panel from FoundationOne. In work published in 

 we hypothesized that because of germline variant contamination, tumor-only sequencing panels likely lead to more pronounced TMB inflation in non-European patients relative to European patients. We leveraged 3 different cohorts: The Cancer Genome Atlas, DanaFarber Cancer Institute, and Memorial Sloan Kettering Cancer Center, all of patients diagnosed with solid tumors. Results showed that tumor mutational biomarker calculation can be inflated if based on tumor-only sequencing, especially in non-European patients. They further showed that this impacts clinical outcomes among patients treated with ICIs. Similar to patients with low TMB, patients with falsely high TMB estimates have significantly worse outcomes compared with patients with true TMB-high tumors when treated with ICIs. We then went on to develop and validate a methodology to calibrate TMB derived from tumor-only sequencing platforms. This work has gained widespread recognition globally, led to invited talks at American Association for Cancer Research, Korean Society of Medical Oncology, and Tempus grand rounds, and has been highlighted in more than 10 media outlets, with several editorials published in Cancer Cell, Nature, and Nature Reviews Genetics. 

Different ancestries lead to varying dispositions. 

 interrogating germline mutations in patients with kidney cancer across different ancestries and highlighting that European and Black patients have different germline mutations that predispose them to kidney cancer. From an epigenetic standpoint, I have pioneered work that maps the epigenetic landscape of 3 subtypes of renal cell carcinoma (RCC): clear cell, chromophobe, and papillary; using different sequencing techniques to map the chromatin and transcriptional landscapes. Our team showed that the epigenome of chromophobe RCC differs from that of clear cell and papillary. Along with the team, we developed an integrated approach that identified 50 candidate histology-specific master transcription factors, which can be further leveraged to better understand RCC pathogenesis. We also leveraged a methodology based on preferential transcription of certain gene alleles, termed allelic imbalance, that can nominate and prioritize causal risk single-nucleotide polymorphisms that are likely to alter transcription factor binding sites.

Finally, I have spent many of my research efforts on underserved populations, which also spans people living with HIV (PWH). PWH are more likely to develop and/or die from cancer vs people living without HIV (PWOH). 

ICIs changed the cancer treatment paradigm, but PWH have either been excluded from clinical trials or included with stringent inclusion criteria. As such, addressing the safety and efficacy of ICIs and other systemic treatments in PWH remains of utmost importance as oncologists expand treatment options for PWH. Where trials fall short or lag behind, real-world studies present an opportunity to address knowledge gaps and guide clinical decision-making for PWH. 

Cancer Therapy using Checkpoint inhibitors in PWH-International (CATCH-IT) is an international consortium focused on the outcomes of PWH receiving ICIs. The consortium consists of 33 national and international cancer centers focused on improving the care for PWH.

In the first study from CATCH-IT, the team investigated the safety and efficacy of ICIs in 451 PWH. They showed that ICIs were safe with no unexpected adverse effects. Moreover, they showed that clinical outcomes, including overall survival and progression-free survival, were similar among PWH and PWOH. This work, now published in the

supports inclusion of PWH in ICI-based trials and motivates clinicians to offer ICIs to patients.

Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N Engl J Med. 2021;384(2):185-187. doi:10.1056/NEJMc2030638 

Nassar AH, Adib E, Abou Alaiwi S, et al. Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors. Cancer Cell. 2022;40(10):1161-1172.e5. doi:10.1016/j.ccell.2022.08.022 

Abou Alaiwi S, Nassar AH, Adib E, et al. Trans-ethnic variation in germline variants of patients with renal cell carcinoma. Cell Rep. 2021;34(13):108926. doi:10.1016/j.celrep.2021.108926 

Nassar AH, Abou Alaiwi S, Baca SC, et al. Epigenomic charting and functional annotation of risk loci in renal cell carcinoma. Nat Commun. 2023;14(1):346. doi:10.1038/s41467-023-35833-5 

El Zarif T, Nassar AH, Adib E, et al. Safety and activity of immune checkpoint inhibitors in people living with HIV and cancer: a real-world report from the cancer therapy using checkpoint inhibitors in people living with HIV-International (CATCH-IT) Consortium. J Clin Oncol. Published online May 16, 2023. doi:10.1200/ JCO.22.02459

Articles

Population genetics integrates genetics and large-scale electronic health record data to identify meaningful biomarkers of treatment consequences and develop algorithmic models to support clinical decision-making. 

Understanding the Impact of Population Genetics on Cancer Treatment

Amin Nassar, MD, a hematology/oncology fellow, Yale University, Yale School of Medicine, discusses findings from a retrospective study of the use of EGFR TKI therapy, durvalumab (Imfinzi), or observation following concurrent chemoradiation in patients with unresectable, stage III non–small cell lung cancer (NSCLC) harboring 

Data presented at the 2023 ASCO Annual Meeting showed that EGFR TKIs were associated with significantly longer disease-free survival compared with durvalumab, and there was no difference measured between durvalumab and observation. In the EGFR TKI arm (n = 34), the median DFS was 40.0 months (95% CI, 26.9–not reached) compared with 14.0 months (95% CI, 10.6-48.2) in the durvalumab arm (n = 34) and 10.2 months (95% CI, 5.3-25.4) in the observation arm (n = 21). The 24-month DFS rates were 86%, 28%, and 29%, respectively.

The multicenter, retrospective study included patients with unresectable stage III, locally advanced NSCLC with 

 sensitizing mutations who received at least 2 cycles of platinum-based chemotherapy concurrently with radiation, Nassar begins. Additionally, patients were not permitted to have experienced disease progression prior to initiation of an EGFR TKI, durvalumab, or observation. The study evaluated DFS, overall survival (OS), and adverse effects (AEs), Nassar explains. Although OS served as a co-primary end point with DFS, the medium follow-up was not sufficient to access OS between the 3 arms, Nassar says.

Regarding safety, 18% of patients treated with an EGFR TKI discontinued treatment due to AEs, compared with 26% of patients in the durvalumab arm. One patient (2.9%) in the TKI arm experienced a grade 3 or higher treatment-related AE vs 2 patients (5.9%) in the durvalumab arm.

Amin Nassar, MD, discusses findings from a retrospective study of the use of EGFR TKI therapy, durvalumab, or observation following concurrent chemoradiation in patients with unresectable, stage III non–small cell lung cancer harboring EGFR mutations.


Amin Nassar, MD

Articles

Bou Farhat and Nassar on the Use of NGS Mutation Signature vs IHC for Identifying dMMR Tumors

Dr Nassar on MMR Determination by IHC and NGS in CRC and Endometrial Cancer

Understanding the Impact of Population Genetics on Cancer Treatment

Dr Nassar on Treatment Options After Chemoradiation in Unresectable, Stage III, EGFR-Mutated NSCLC