A recent study published in Nature highlights the complex interplay between intratumoral heterogeneity and acquired therapy resistance in a patient with metastatic prostate cancer. The case underscores the challenges of treating advanced cancers with diverse genomic profiles and the need for personalized treatment strategies.
Clinical History
The patient, a 76-year-old man, initially presented with hematuria and a high prostate-specific antigen (PSA) level of 5786 ng/ml. He was diagnosed with high-grade prostate adenocarcinoma (Gleason 5+4=9) with widespread metastases. Initial next-generation sequencing (NGS) revealed a genomic deletion of MSH2, indicating mismatch repair deficiency (MMRd). The patient was initially treated with androgen deprivation therapy (leuprolide), followed by docetaxel and abiraterone, with limited response. Subsequently, treatment with the anti-PD1 agent nivolumab led to a significant PSA decline (99.4%) and tumor volume reduction. However, resistance developed within four months.
Enzalutamide was added to nivolumab, resulting in a 93% PSA decline and sustained response for several years. Upon progression, subsequent treatments including cabazitaxel, bipolar androgen therapy, and ipilimumab combined with nivolumab showed no notable response. A biopsy of a cervical lymph node seven years post-diagnosis revealed prostate adenocarcinoma with retained expression of MMR proteins, contrasting with the initial MMRd diagnosis.
Genomic Analysis Reveals Intratumoral Heterogeneity
Further investigation of the primary tumor revealed two distinct regions: one with MMRd (MSH2 loss) and another with MMR proficiency (MMRp). Whole-exome sequencing showed that the late metastatic disease was derived from the MMRp region of the primary tumor, which was clonally distinct from the initial MMRd region. The MMRp region also harbored a BRCA2 deletion. Based on the BRCA2 loss, the patient was treated with olaparib, resulting in a 63% PSA decline and near-resolution of liver metastases. However, resistance eventually developed, and ctDNA analysis revealed mutations in AR, CHEK2, NF1, PIK3CA, and TP53.
Implications for Treatment Strategies
This case illustrates how intratumoral heterogeneity can drive acquired therapy resistance. The initial response to nivolumab targeted the MMRd component of the tumor, while the later development of resistance was linked to the outgrowth of an MMRp subclone. The subsequent response to olaparib highlights the potential of targeting specific genomic alterations, such as BRCA2 loss, even in the context of heterogeneous disease. The study underscores the importance of comprehensive genomic profiling to identify actionable targets and tailor treatment strategies to the evolving genomic landscape of individual tumors. Understanding the clonal relationships and the dynamic changes in tumor composition is crucial for overcoming therapy resistance and improving outcomes in advanced prostate cancer.
