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Recent advances in pancreatic cancer: From screening protocols to precision medicine paradigms
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Pancreatic ductal adenocarcinoma, or PDAC, is the third most common cause of cancer-related death in the United States, with a median 5-year survival rate of only 9%.
Incidence of this cancer is rising, an effect of an aging population, improved diagnostics and the so-called “diabesity” epidemic.
However, there have been several recent advances in PDAC, from efforts at cancer interception in high-risk cohorts to implementation of precision medicine paradigms, as well as newly reported, practice-changing data in surgically resected patients.
Identifying high-risk cohorts for screening
An important strategy for improving outcomes of patients with PDAC is the development of effective screening protocols to identify patients at a potentially resectable stage of disease.
However, considering the low incidence of PDAC in the general population, a population-based screening strategy is likely to be futile. Therefore, many investigators have advocated for selective screening of individuals at an increased risk for PDAC, such as those with a strong family history or an identifiable germline predisposition.
In a retrospective study of the Cancer of the Pancreas Screening (CAPS) program, Abe and colleagues found the likelihood of developing PDAC or a precursor lesion with high-grade dysplasia was significantly higher among individuals with a germline mutation in a PDAC susceptibility gene, such BRCA2, than among individuals with a strong family history but no identifiable mutation. Further, patients aged younger than 55 years diagnosed with PDAC or high-grade dysplasia were all germline mutation carriers.
With the recent revision of the National Comprehensive Cancer Network guidelines recommending universal germline testing for all patients with PDAC (ie, “index cases”), a pool of unaffected mutation carriers, primarily comprised of first-degree relatives, may soon become easier to identify. But, the effectiveness of any screening protocol will be dependent on index cases sharing their mutation information with at-risk relatives so they, too, may undergo germline testing — a process known as “cascade testing.”
The recently opened Stand Up to Cancer Pancreatic Cancer Collective-funded GENERATE study — available at www.generatestudy.org — is one avenue by which first-degree relatives of mutation-positive index cases can get tested from the convenience of their home, thanks to a partnership with Color Genomics, which will provide multigene testing at no charge to study participants. Mutation carriers can then be channeled into screening programs such as CAPS for longitudinal follow-up.
The actionable genome
Revisions to the NCCN guidelines for PDAC not only recommend germline testing, but also tumor genomic profiling for patients with locally advanced/metastatic disease if they are candidates for anticancer therapy.
Although pairing genomic alterations with specific chemotherapeutic regimens has demonstrated improved patient outcomes for several malignancies, such as lung cancer, the same level of success has not been achieved with PDAC. Aside from KRAS, TP53, CDKN2A and SMAD4 — none of which is currently targetable — PDAC is characterized by marked genomic heterogeneity with additional mutations present at low-level frequencies (< 5%). However, these low-level alterations might be “actionable” based on parallel studies in other tumor types.
In Gastroenterology, Singhi and colleagues reported the results of real-time targeted genomic profiling of nearly 3,600 patients with PDAC. Researchers utilized a large targeted gene sequencing panel to include pan-cancer genomic alterations that are known to be clinically relevant in not only PDAC, but a multitude of tumor types.
The authors found 17% of PDACs harbored known genomic alterations that may confer susceptibility to current anticancer therapy. Moreover, these genomic alterations can be subdivided into two categories: (1) targetable alterations in the RTK/Ras/MAPK signaling pathway in the form of kinase gene fusions, amplifications and intragenic deletions; and (2) predictive biomarkers for treatment in the DNA damage repair (DDR) pathway, such as the BRCA-FANC family of genes that are known to confer sensitivity to platinum-based cytotoxic regimens and PARP inhibition.
Although this study does not address obstacles in implementing precision medicine among patients with PDAC, it does provide a compendium of known genomic alterations for PDAC and serves as a clinical resource to guide future therapy for patients undergoing targeted genomic profiling.
In fact, as recently as February, AstraZeneca announced that POLO — the pivotal phase 3 trial of maintenance olaparib (Lynparza, AstraZeneca), a PARP inhibitor, in patients with germline BRCA mutations whose disease had not progressed on frontline platinum-based therapy — had met its primary endpoint of significantly enhancing PFS vs. placebo, providing a new therapeutic option for patients with PDAC and DDR-defective tumors. The details of the POLO study will be presented at a plenary session at this year’s ASCO Annual Meeting.
Advances in therapeutics of localized pancreatic cancer
Although considerable focus on improving treatment outcomes in PDAC has centered on metastatic disease, some of the largest gains in survival have come in the minor subset of patients with surgically resectable tumors.
Foremost amongst this has been the recent trial comparing modified FOLFIRINOX (mFOLFIRINOX) with gemcitabine in the adjuvant setting from two consortia in France and Canada — referred to as the PRODIGE trial.
In this practice-changing study, the mFOLFIRINOX regimen resulted in a median OS of 54 months, which represents a new threshold for survival in the adjuvant setting. As a caveat, median OS in the control gemcitabine arm was 35 months, itself substantially longer than previously reported and reflecting a combination of astute patient selection and the impact of receiving mFOLFIRINOX on progression.
This trial dovetailed into a previously reported successful trial of adjuvant gemcitabine and capecitabine (“gem-cape”) vs. gemcitabine alone in resected PDAC from the European ESPAC consortium, where the combination regimen had a median OS of 28 months.
In contrast, unpublished data released by Celgene reported that adjuvant gemcitabine plus nab-paclitaxel (Abraxane, Celgene) failed to meet its primary endpoint of improved PFS compared with gemcitabine alone in the phase 3 APACT study, albeit there was “nominally significant” improvement in OS. Details of the APACT study also will be presented at the upcoming ASCO meeting.
Overall, these trials leave oncologists with several choices in the adjuvant setting, including mFOLFIRINOX and other 5-FU-based regimens, “gem-cape,” and even gemcitabine monotherapy, based on patient tolerability.
The next frontier in the adjuvant setting will focus on maintenance treatments beyond the mandated duration of cytotoxic regimen for patients who have not progressed, for example with tumor neoantigen-specific personalized vaccines or other “low-intensity” immunotherapy protocols, as patient outcomes continue to improve in this disease.
References:
Abe T, et al. J Clin Oncol. 2019;doi:10.1200/JCO.18.01512.
Bailey P, et al. Nature. 2016;doi:10.1038/nature16965.
Canto MI, et al. Gut. 2013;doi:10.1136/gutjnl-2012-303108.
Conroy T, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809775.
Neoptolemos JP, et al. Lancet. 2017;doi:10.1016/S0140-6736(16)32409-6.
Raphael BJ, et al. Cancer Cell. 2017;doi:10.1016/j.ccell.2017.07.007.
Singhi AD, et al. Gastroenterology. 2019;doi:10.1053/j.gastro.2019.02.037.
For more information:
Aatur D. Singhi, MD, PhD, is assistant professor of pathology in the division of molecular and genomic pathology and member of the Gastrointestinal Pathology Center of Excellence at University of Pittsburgh Medical Center. He can be reached at Scaife Hall, Room 616.2, 200 Lothrop St., Pittsburgh, PA 15213; email: singhiad@upmc.edu.
Anirban Maitra, MBBS, is professor of translational molecular pathology and scientific director of Sheikh Ahmed Center for Pancreatic Cancer Research at The University of Texas MD Anderson Cancer Center. He can be reached at MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.
To contribute to this column or suggest topics, email Wafik S. El-Deiry, MD, PhD, FACP, at wafik.eldeiry@gmail.com.
Disclosures: Singhi and Maitra report no relevant financial disclosures.