1. Hepp, Rebecca

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The growing promise of targeted therapy for many cancers has put tumor genetics in the spotlight. For relapsed small cell lung cancer (SCLC), full genomic characterization has remained elusive. The literature as it stands today focuses mostly on treatment-naive patients-leaving many questions unanswered for refractory cases.

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"Until recently, few studies have been able to perform genomic profiling studies of recurrent SCLC due to limited availability of tissues," according to Huizi Chen, MD, PhD, a Physician Scientist Training Program trainee at The Ohio State University's Wexner Medical Center. "We leveraged our Rapid Research Autopsy Program to obtain metastatic cancer tissues for genomic characterization through next-generation sequencing from patients who have died from recurrent SCLC."


Their findings, presented at the American Association for Cancer Research's (AACR) annual meeting, are an important step toward better understanding the molecular mechanisms of relapse, metastatic dissemination, and chemoresistance (Abstract 748/22).


"By studying the genetics of recurrent SCLC, we hope to identify mutations and signaling pathways that drive recurrence and acquired therapeutic resistance," Chen noted. "We hope to gain a better molecular understanding of how recurrence and resistance develop and translate this understanding into the design of rationale therapies for this deadly cancer."


A Population In Need

Ongoing research is crucial for these patients, considering lung cancer stands as the leading cause of cancer death in the U.S.-and approximately 15 percent of all lung cancer patients are diagnosed with SCLC, according to Chen (Ther Adv Med Oncol 2014;6(2):69-82). Luckily, the incidence of SCLC has decreased over the years, likely due to a decrease in the use of tobacco products, as nearly all patients with SCLC have a positive smoking history (Transl Lung Cancer Res 2016;5(1):26-38). Still, 2015 saw 260,000 new cases worldwide.


While many patients with metastatic lung cancer initially respond well to first-line therapies such as platinum-doublet chemotherapy, the diagnosis has a poor prognosis with a 5-year overall survival rate of only 5-10 percent. The initial treatment response is often brief, and most patients either progress during initial therapy or relapse soon after completing treatment. Those who initiate a second-line therapy usually only survive another 4 or 5 months.


What little treatment progress has been made over the last 20 years has revolved around adding concurrent radiotherapy to the chest and prophylactic cerebral irradiation. But today, concurrent immunotherapy in addition to chemotherapy has finally provided a chance for increased survival, albeit modest.


The FDA approved the first immunotherapy for SCLC, atezolizumab, on March 18, 2019. In clinical trials, frontline therapy with the immune checkpoint inhibitor in addition to standard chemotherapy provided a median survival of 12.3 months compared with 10.6 in the chemotherapy plus placebo group (N Engl J Med 2018;379:2220-2229). The immunotherapy delayed progression by about a month for most patients, too.


The new treatment is promising, but a deeper knowledge of the mechanisms behind treatment relapse could pave the way for more targeted therapy.


Profiling Recurrent SCLC

The OSU team, led by Chen, began with a well-established notion that inactivation of tumor suppressor genes TP53 and RB1 is a genetic marker of SCLC. Previous research has also revealed other genes associated with SCLC pathogenesis, including CREBBP, MLL, NOTCH1-4, SOX2, and MYC. But what happens to these candidate driver genes during treatment is still unknown.


"By understanding differences in the genetic landscape of untreated versus treated SCLC, we hope to identify mutations in key signaling pathways that endow cancer cells the ability to metastasize and become resistant to treatment, which are properties of more evolved cancer cells that are likely caused by different mechanisms than those involved in the initial development of cancer," Chen explained.


Unfortunately, this type of research hinged on access to donor tissue, which Chen's team accessed from their institution's autopsy program.


"From a clinical perspective, we have been amazed, encouraged, grateful, and humbled by the willingness of our patients to donate their bodies for cancer research after death, thereby enabling access to precious tissue samples," Chen explained. "We encourage every medical oncologist to have an informed discussion with patients regarding opportunities to participate in cancer research, whether through clinical trials or body donation."


The team's resulting gene sequencing confirmed genomic alterations in TP53 in all of the tumor samples and, to a lesser extent, RB1 post-treatment. They also detected deletion of APC, a tumor suppressor gene, in most samples, which the study authors note aligns with recent results published by another research group that showed WNT signaling affects chemoresistance. In one of the five patients they sequenced, the team detected deletion of PTEN, which may be a possible driver of organ-specific metastases, according to Chen.


By studying the tumors of three patients both before and after treatment, the researchers discovered multiple clones of tumor cells in both samples, suggesting "tumor heterogeneity occurs early in SCLC development and is subsequently maintained through branching evolution," Chen explained.


Next Steps

Chen is hopeful that studies such as this one "will lay the foundation for pre-clinical studies in the appropriate model systems that will ultimately guide the development of targeted and more effective therapies for recurrent SCLC."


But her findings are just the beginning. The team hopes to analyze tumor tissues from significantly more recurrent SCLC patients and take a closer look how the specific gene mutations they have uncovered affect transcription. Chen's interests also include analyzing the epigenome, "which involves reversible changes to the genome that affect gene transcription such as DNA methylation or histone modifications, of recurrent SCLC," she explained.


"By integrating our knowledge of recurrent SCLC at these various molecular levels, we will potentially be able to develop therapies against multiple vulnerabilities," Chen emphasized.


With so few therapies providing any significant hope for SCLC patients, this research is a welcome first step toward a better outlook for these patients. Currently, most patients with recurrent SCLC die within a short period of relapse due to the aggressiveness of the cancer, according to Chen-but gene sequencing and well-designed clinical trials will one day change that.


Rebecca Hepp is a contributing writer.