Pancreatic cancer accounts for almost as many deaths (466,000) as cases (496,000) because of its poor prognosis. It is the seventh leading cause of cancer death in both men and women (1). Considering that the rates of this tumor type are rather stable relative to the declining rates of breast cancer, it has been projected that pancreatic cancer may surpass breast cancer as the third leading cause of cancer death by 2025 in a study of 28 European countries (1,2).
“Only 20% of patients with pancreatic cancer have tumors which are considered surgically resectable at diagnosis. Since pancreatic cancer is mostly diagnosed at advanced stages of disease, 80% of these patients relapse and ultimately develop metastasis. The identification and development of more effective and targeted treatment strategies will ultimately improve pancreatic survival rates,” says Teresa Macarulla, Principal Investigator of VHIO’s Upper Gastrointestinal and Endocrine Tumors Group, Medical Oncologist at the Vall d’Hebron University Hospital (HUVH), and Head of our Upper Gastrointestinal and Endocrine Tumors Translational Research Laboratory led by Senior Researcher and Preclinical Team Leader Tian Tian.
Selected to first outing at the 2023 Annual Meeting of the American Society of Clinical Oncology (ASCO), 2-6 June (Chicago, IL) as poster presentations, the following three VHIO-led studies have revealed new insights and mapped possible next directions in the treatment of pancreaticobiliary cancers.
Advancing insights into the molecular characteristics of early-onset pancreatic cancer
“Widely reported in the literature, and the subject of a recent editorial article in The Lancet Gastroenterology & Hepatology (3), the incidence of early-onset pancreatic cancer is increasing at an alarming rate. The clinical and genomic features of pancreatic cancer in people aged fifty years or under remain poorly defined,” says Florian Castet, Clinical Investigator of VHIO’s Upper Gastrointestinal and Endocrine Tumors Group, Medical Oncologist at HUVH, and lead author of a study (4) that was presented today at ASCO 2023.
Carried out in collaboration with VHIO’s Cancer Genomics and Oncology Data Science (ODysSey) Groups —directed by Ana Vivancos and Rodrigo Dienstmann, respectively— and investigators of our Upper Gastrointestinal and Endocrine Tumors Translational Research Laboratory, the researchers sought to characterize early-onset disease and study its implications for treatment and prognosis.
They performed a retrospective analysis of 336 patients—139 patients with early-onset pancreatic cancer (≤ 50 years of age) and a control group of 197 average-age-onset patients (≤ 70 years of age). The investigators correlated baseline patient characteristics, tumor molecular profiling, germline genetic alterations, survival and treatment outcomes.
“We observed a lower prevalence of KRAS-mutant tumors in the early-onset group versus the control group. Of note, early-onset tumors were enriched in potentially actionable alterations when compared with the average-age-onset group. Of the 336 patients, 294 were diagnosed with or eventually presented metastasis— 130 in the early-onset cohort versus 164 in the control group,” adds Castet.
These data indicate that patients with early-onset pancreatic cancer harbor unique clinical and molecular features and may particularly benefit from precision-based oncology approaches. They also underpin the importance of identifying and developing more effective and targeted treatment strategies against pancreatic cancer.
Overall survival vs. progression-free survival in biliary tract cancer clinical trials
Cancer of the bile ducts, also called cholangiocarcinoma, is a heterogeneous spectrum of diseases that are commonly diagnosed at advanced stages. Overall survival is the traditional measurement of patient outcomes in randomized controlled clinical trials.
“The increasing use of subsequent lines of therapies and cross-over designs may however confound the effect of treatment. On behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors, we explored the use of progression-free survival as a surrogate endpoint of overall survival, both at the trial and patient levels,” says Carles Fabregat, Clinical Investigator of VHIO’s Upper Gastrointestinal and Endocrine Tumors Group, Medical Oncologist at HUVH, and first author of a VHIO-led study that was also presented today as a poster (5) at ASCO 2023.
The investigators conducted a systematic review of patients with advanced bile duct tumors included in the Spanish RETUD registry of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) and analyzed a total of 1992 clinical trials. At the trial level they observed that treatment effects on progression-free survival moderately correlated with overall survival, indicating that a 31% decreased risk of disease progression would likely lead to a clinically significant overall survival benefit in a hypothetical clinical trial including 400 patients.
“At the patient level, we found that progression-free survival and overall survival were strongly correlated in a real-world cohort. Future validation of this criterion is therefore warranted in patients treated in the context of randomized clinical studies,” adds Fabregat.
Seeking out biomarkers of response to platinum-based chemotherapy
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year survival rate of less than 10%. The optimal stratification of these patients is key in improving outcomes in this patient population.
Mutations affecting DNA damage repair (DDR) genes associate with clinical benefit from platinum-based chemotherapy (PBC) in patients with ovarian and breast cancer. Alterations in DDR genes including BRCA1/2, PALB2, ATM, ATR, CHK1 or RAD51, are found in about 15% of PDAC. To date it has not been well established if patients with advance disease harboring DDR gene mutations could benefit more from PBC.
A study (6) led by Tian Tian, Senior Researcher and Preclinical Team Leader of VHIO’s Upper Gastrointestinal and Endocrine Tumors Translational Research Laboratory,
compared the prevalence of DDR mutations between those patients who benefited from PBC and those who did not. Carried out in collaboration with VHIO’s Upper Gastrointestinal and Endocrine Tumors and Cancer Genomics Groups—directed by Teresa Macarulla and Ana Vivancos respectively—the investigators retrospectively analyzed samples from patients with advanced PDAC who received treatment with PBC at Vall d’Hebron from 2008-2022. A total of 132 patients were included in this study.
In this cohort, among the 88 patients who were identified as responders, 42 patients had genomic alterations in BRCA1/2 or PALB2, and 10 patients had mutations in other DDR genes. Among non-responders, only 17 patients showed DNA damage repair gene alterations.
“Those patients with DNA damage repair gene mutations showed significantly longer progression-free survival and overall survival compared with those without alterations. Our data show that genomic mutations in DDR genes significantly associated with clinical benefit of platinum-based chemotherapy in patients with advanced pancreatic ductal adenocarcinoma,” says Tian Tian, first author of this study.
“Our results support the use of DNA damage repair genes as an additional decision-making tool for the stratification of these patients even before standard of care chemotherapies,” concludes Tian.
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References:
- Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249.
- Ferlay J, Partensky C, Bray F. More deaths from pancreatic cancer than breast cancer in the EU by 2017. Acta Oncol. 2016 Sep-Oct;55(9-10):1158-1160.
- Cause for concern: the rising incidence of early-onset pancreatic cancer. Lancet Gastroenterol Hepatol. 2023 Apr;8(4):287.
4. Clinical and genomic characterization of early-onset pancreatic cancer. Florian Castet, Carles Fabregat Franco, Gloria Castillo, Victor Navarro, Eduardo García-Galea, Alexandre Sierra, Ana Carmona-Alonso, Tian Tian, Ana Vivancos, Teresa Macarulla.
Presenter: Florian Castet, Gastrointestinal and Endocrine Tumor Unit, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital (HUVH), Vall d’Hebron Barcelona Hospital Campus.
Session Type: Poster Session
Session Track: Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary.
Abstract #: 4018
Poster Bd #: 339
Citation: J Clin Oncol 41, 2023 (suppl 16; abstr 4018).
DOI: 10.1200/JCO.2023.41.16_suppl.4018
5. Progression-free survival as a surrogate endpoint of overall survival in advanced biliary tract cancer: A meta-analysis of randomized trials and individual-patient level correlation. Carles Fabregat Franco, Florian Castet, Adelaida La Casta, Jorge Adeva, Alfredo Castillo, Andrés Muñoz, Paloma Peinado, Eva Martínez de Castro, Miriam Lobo, Monica Granja, Rosa Maria Rodriguez-Alonso, Ana Fernandez Montes, Ruth Vera, Javier Gallego, Begoña Graña, Ismael Ghanem, Inmaculada Alés, Raquel Molina, Teresa Macarulla, Enrique Aranda.
Presenter: Carles Fabregat Franco, Gastrointestinal and Endocrine Tumor Unit, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital (HUVH), Vall d’Hebron Barcelona Hospital Campus.
Session Type: Poster Session
Session Track: Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary.
Abstract #: 4101|
Poster Bd #: 422
Citation: J Clin Oncol 41, 2023 (suppl 16; abstr 4101)
DOI: 10.1200/JCO.2023.41.16_suppl.4101
6. Retrospective evaluation of the value of DNA damage repair gene signature in response to platinum-based chemotherapy in advanced pancreatic ductal adenocarcinoma. Tian Tian, Carles Fabregat Franco, Gloria Castillo, Florian Castet, Helena Verdaguer, Daniel Lopez Valbuena, Ana Carmona-Alonso, Ana Vivancos, Teresa Macarulla.
Presenter: Tian Tian, Preclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO).
Session Type: Poster Session
Session Track: Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary.
Abstract #: 4137
Poster Bd #: 458
Citation: J Clin Oncol 41, 2023 (suppl 16; abstr 4137)
