Molecular Profiling and Precision Treatment in Pancreatic Cancer

Wungki Park, MD, Memorial Sloan Kettering Cancer Center, New York, New York, reviews the key clinical lessons from a case of PALB2-associated, homologous recombination–deficient pancreatic cancer to illustrate how molecular profiling can inform treatment selection throughout the disease course.

He discusses the significance of biallelic PALB2 loss in predicting platinum sensitivity, the role of germline and tumor genomic testing, and the emerging potential of KRAS G12D–targeted therapies in appropriately selected patients. He also highlights the importance of integrating tumor biology, clinical trial opportunities, local therapies, and patient preferences to deliver personalized, precision care for patients with pancreatic cancer.

Transcript: 

Hello, my name is Wungki Park. I'm a gastrointestinal medical oncologist at Memorial Sloan Kettering, where I treat patients with pancreatic cancer and biliary tract cancer. Today, I'd like to discuss a case that highlights how molecular profiling is increasingly guiding treatment decisions in pancreatic cancer.

This case involves a 45-year-old woman with a germline PALB2 mutation and a strong family history of breast, ovarian, and prostate cancers. She had undergone appropriate genetic counseling and risk-reduction surgeries prior to her cancer diagnosis. Following surgical resection, her tumor was found to have high-risk features. Importantly, tumor sequencing demonstrated biallelic loss of PALB2. This is a key concept. In homologous recombination deficiency, it is not simply the presence of a mutation but the loss of function of both alleles that drives therapeutic sensitivity.

She received adjuvant FOLFIRINOX and later developed metastatic recurrence. Given the homologous recombination–deficient biology of her tumor, she was treated with gemcitabine plus cisplatin and achieved a durable response lasting nearly 2 years. This reinforces an important teaching point that PALB2-mutant pancreatic cancer behaves similarly to BRCA-associated pancreatic cancer in terms of platinum sensitivity.

At the time of disease progression, she enrolled in a clinical trial evaluating an investigational KRAS G12D–targeted inhibitor. These therapies remain investigational and are currently available only through clinical trials, but early data suggest meaningful activity in selected patients. She achieved a partial response and maintained an excellent quality of life for approximately nine months. At the time of progression, her disease remained limited to a small number of liver lesions.

We therefore pursued a local treatment approach using radiation therapy, which allowed her to have a break from systemic treatment. This reflected an individualized strategy based on both the biology of her disease and her personal preferences. When she subsequently progressed again, we rechallenged her with platinum-based chemotherapy, guided by her excellent prior response and improved treatment tolerance. This decision also incorporated her personal goals, including minimizing treatment-related toxicity that might interfere with her professional responsibilities. 

There are several important learning points from this case. First, PALB2, which stands for Partner and Localizer of BRCA2, is an important homologous recombination repair gene and should be recognized when selecting therapy. Second, biallelic loss is a critical determinant of treatment response. This finding is often underreported in routine clinical practice but should be carefully evaluated whenever possible. Third, platinum-based chemotherapy remains the foundation of treatment for patients with homologous recombination–deficient pancreatic cancer. Fourth, enrollment in clinical trials should be strongly considered, particularly as emerging therapies such as KRAS-targeted inhibitors continue to evolve.

Finally, this case emphasizes the importance of genetic counseling and germline testing—not only for treatment selection for the patient but also for identifying cancer risk in family members. 

Overall, integrating tumor biology, clinical context, and patient goals allows us to deliver increasingly personalized and precise care for patients with pancreatic cancer. Thank you very much.