Pierre Laurent-Puig, MD

The invited discussant of the FOCUS4-C trial was Pierre Laurent-Puig, MD, Professor of Medicine, Université de Paris, Institut du Cancer Paris CARPEM. According to Dr. Laurent-Puig, the “promising results” for the WEE1 inhibitor adavosertib in colorectal cancer in the FOCUS4-C trial could apply to the fairly sizable group of patients with metastatic colorectal cancer and mutations in both TP53 and RAS.¹

Adavosertib is also being evaluated in platinum-sensitive and platinum-resistant ovarian cancer and in metastatic triple-negative breast cancer. Most of these patient populations have TP53-mutated tumors. The studies have looked for biomarkers of efficacy and have reported some candidate genes, he said.

Understanding WEE1 Inhibition Based on TP53/RAS Mutations

Dr. Laurent-Puig explained how inhibition of WEE1—which is not altered in cancer (mutations occur in < 1% of colon cancer) but is a key player in cancer survival—could be advantageous in patients with colorectal cancer who harbor both TP53 and RAS mutations. The WEE1 kinase family has a crucial role in cell-cycle regulation and DNA-damage identification as well as repair in both nonmalignant and cancer cells.

The rationale for selecting patients for WEE1 inhibition based on TP53/RAS mutations, he said, “is probably a story of synthetic lethality in DNA-damage repair.” In the setting of DNA damage, two pathways become activated: one involves TP53 and the tumor expressor protein P21, which inhibits the cyclin-dependent kinase (CDK) 2/cyclin A/E complex, which in turn inhibits cell-cycle transition from the G1 to the S phase. The second pathway involves CHEK1/WEE1, which inhibits the CDK1/cyclin B complex, which subsequently blocks the transition from G2 to M, “allowing repair of DNA and safe mitosis,” Dr. Laurent-Puig added.

The addition of a WEE1 inhibitor into the process essentially allows for all “brakes” to be removed, for the G-to-M phase transition to occur, and for mitotic catastrophe and cell death to be induced, he said.

Findings From a Pooled Series

Dr. Laurent-Puig and his team have studied the clinical correlations for TP53 mutation, RAS mutation, and the two together. In sequencing 2,407 patients with stage III colon cancer from pooled series, they found the double mutation to be present in 712 patients (29.5%) and to be significantly more frequent in female patients (48%), in proximal tumors (43%), and in recurrent cancers in patients with stage III disease (37%) (unpublished data). “The finding of [frequency in] proximal tumors is important, because WEE1 seems to be more efficient in distal colon cancer,” he noted.

Correlating the mutation profile with clinical outcomes in the pooled series, they found the double mutation conferred the lowest disease-free survival, whereas RAS-mutated tumors followed that. The best outcome was seen in the double wild-type tumors, followed by TP53-mutated tumors. These results align with data from the FOCUS4-C trial, which also showed that the double mutation confers a poor prognosis.

Dr. Laurent-Puig expects the next step with adavosertib will be to examine it in conjunction with chemotherapy and to identify biomarkers of efficacy beyond tumor location. 

DISCLOSURE: Dr. Laurent-Puig reported personal financial relationships with AstraZeneca, Amgen, Biocartis, Sanofi, Roche, Servier, Pierre Fabre, Institut Lilly, and Methys DX.

REFERENCE

1. Seligmann JF, Fisher DJ, Brown LC, et al: Inhibition of WEE1 is effective in TP53 and RAS mutant metastatic colorectal cancer: A randomised phase II trial (FOCUS4-C) comparing adavosertib (AZD1775) with active monitoring. ESMO Congress 2021. Abstract 382O. Presented September 18, 2021.