Case Presentation: Molecularly Guided Therapy for Homologous Recombination–Deficient Pancreatic Cancer
Patient Case:
A 45-year-old woman with a strong family history of cancer, including an aunt diagnosed with breast cancer at age 40, a mother with ovarian cancer at age 50, and an uncle with prostate cancer, presented with jaundice and was diagnosed with resectable pancreatic adenocarcinoma. She had previously undergone germline genetic testing at age 35 after genetic counseling, which identified a pathogenic PALB2 mutation. Based on this finding, she underwent prophylactic bilateral mastectomy and total abdominal hysterectomy with bilateral salpingo-oophorectomy after completing childbearing.
She underwent surgical resection and was found to have T2N1 pancreatic ductal adenocarcinoma. Tumor sequencing identified KRAS G12D, TP53, and CDKN2A alterations, and further analysis demonstrated loss of heterozygosity of PALB2, consistent with biallelic loss and a homologous recombination–deficient phenotype.
She completed 6 months of adjuvant modified FOLFIRINOX and subsequently enrolled in an adjuvant PARP inhibitor clinical trial. Approximately 3 years later, she developed metastatic recurrence involving the liver.
Given her homologous recombination–deficient tumor, she was treated with gemcitabine and cisplatin, achieving durable disease control for nearly 18 months before treatment was discontinued because of cumulative sensory neuropathy and impaired dexterity. At disease progression with liver and lung metastases, she enrolled in a clinical trial of an investigational KRAS G12D-targeted inhibitor, achieving a confirmed partial response with a 60% reduction in tumor burden by RECIST criteria. She remained on therapy for 10 months while maintaining an excellent quality of life.
Following progression, her disease remained oligometastatic in the liver with stable CA 19-9 levels. She underwent palliative radiotherapy to sites of progression and elected to take a systemic treatment break, which lasted approximately 12 months. With subsequent slow disease progression and rising CA 19-9 levels, she was re-challenged with gemcitabine and cisplatin based on her prior response, the underlying tumor biology, and her treatment goals, including minimizing alopecia because of her profession as a healthy food recipe influencer. She has now remained on this regimen for more than 10 months with continued disease control and good quality of life.
