GENETICS AND TARGETED TREATMENT OF CUP

In a study reported in JAMA Oncology, Ross et al found potentially targetable genomic alterations in most carcinomas of unknown primary site using comprehensive genomic profiling. Adenocarcinomas of unknown primary site frequently harbored receptor tyrosine kinase/Ras/MAPK pathway alterations.  

The study involved findings from genomic profiling of 200 successfully sequenced carcinoma of unknown primary site formalin-fixed paraffin-embedded specimens (mean = 756× coverage), including 125 adenocarcinomas of unknown primary site and 75 carcinomas of unknown primary site without adenocarcinoma features.

Alterations

At least 1 genomic alteration was found in 96% of specimens, with a mean of 4.2 alterations per tumor. The most common alterations were in TP53 (55%), KRAS (20%), CDKN2A (19%), MYC (12%), ARID1A (11%), MCL1 (10%), PIK3CA (9%), ERBB2 (8%), PTEN (7%), EGFR (6%), SMAD4 (7%), STK11 (7%), SMARCA4 (6%), RB1 (6%), RICTOR (6%), MLL2 (6%), BRAF (6%), and BRCA2 (6%).

Targetable Alterations

At least one potentially targetable alteration was found in 169 specimens (85%). Alterations in ERBB2 (10% vs 4%), EGFR (8% vs 3%), and BRAF (6% vs 4%) were more common in adenocarcinoma specimens than in nonadenocarcinoma specimens. Targetable alterations in receptor tyrosine kinase/Ras signaling pathways, including alterations in ALK, ARAF, BRAF, EGFR, FGFR1, FGFR2, KIT, KRAS, MAP2K1, MET, NF1, NF2, NRAS, RAF1, RET, and ROS1, were found in 72% of adenocarcinomas of unknown primary site vs 39% of nonadenocarcinoma carcinomas of unknown primary site (P < .001).

The investigators concluded: “Almost all [carcinoma of unknown primary site] samples harbored at least 1 clinically relevant [genomic alteration] with potential to influence and personalize therapy. The [adenocarcinoma of unknown primary site] tumors were more frequently driven by [genomic alterations] in the highly druggable [receptor tyrosine kinase]/Ras/[MAPK] signaling pathway than the non-[adenocarcinoma carcinoma of unknown primary site] tumors. Comprehensive genomic profiling can identify novel treatment paradigms to address the limited options and poor prognoses of patients with [carcinoma of unknown primary site].”

Jeffrey S. Ross, MD, of Albany Medical College, New York, is the corresponding author for the JAMA Oncology article.

At the time of manuscript submission, all authors were employees and equity holders of Foundation Medicine, Inc, Cambridge, Massachusetts.