Cancer Res Treat.  2022 Oct;54(4):1209-1218. 10.4143/crt.2021.963.

Genomic Correlates of Unfavorable Outcome in Locally Advanced Cervical Cancer Treated with Neoadjuvant Chemoradiation

• Wei Y
• Wei C
• Chen L
• Liu N
• Ou Q
• Yin JC
• Pang J
• Fang Z
• Wu X
• Wang X
• Mu D
• Shao Y
• Yu J
• Yuan S

• KMID: 2534200
• DOI: http://doi.org/10.4143/crt.2021.963

Abstract

Purpose
Neoadjuvant therapy modality can increase the operability rate and mitigate pathological risks in locally advanced cervical cancer, but treatment response varies widely. It remains unclear whether genetic alterations correlate with the response to neoadjuvant therapy and disease-free survival (DFS) in locally advanced cervical cancer.
Materials and Methods
A total of 62 locally advanced cervical cancer (stage IB-IIA) patients who received neoadjuvant chemoradiation plus radical hysterectomy were retrospectively analyzed. Patients’ tumor biopsy samples were comprehensively profiled using targeted next generation sequencing. Pathologic response to neoadjuvant treatment and DFS were evaluated against the association with genomic traits.
Results
Genetic alterations of PIK3CA were most frequent (37%), comparable to that of Caucasian populations from The Cancer Genome Atlas. The mutation frequency of genes including TERT, POLD1, NOS2, and FGFR3 was significantly higher in Chinese patients whereas RPTOR, EGFR, and TP53 were underrepresented in comparison to Caucasians. Germline mutations were identified in 21% (13/62) of the cohort and more than half (57%) had mutations in DNA damage repair genes, including BRCA1/2, TP53 and PALB2. Importantly, high tumor mutation burden, TP53 polymorphism (rs1042522), and KEAP1 mutations were found to be associated with poor pathologic response to neoadjuvant chemoradiation treatment. KEAP1 mutations, PIK3CA-SOX2 co-amplification, TERC copy number gain, and TYMS polymorphism correlated with an increased risk of disease relapse.
Conclusion
We report the genomic profile of locally advanced cervical cancer patients and the distinction between Asian and Caucasian cohorts. Our findings highlight genomic traits associated with unfavorable neoadjuvant chemoradiation response and a higher risk of early disease recurrence.

Keyword

Uterine cervical neoplasms; Neoadjuvant therapy; Pathologic response; Disease-free survival; DNA damage repair

Figure

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  Fig. 1 Distribution of gene alterations correlated with pathologic response. Gene alterations and patient clinical characteristics were shown at the top and bottom, respectively. Patients were separated into three groups, of which H&E stains exhibited < 10%, 10%–50% and 50%–100% viable tumor cells. The BRCA1/2, POLD1, and POLE were genes related to targeted therapy or immunotherapy. PIK3CA hotspot mutations on E542, E545, and H1047 were marked by white asterisks. The 0%–10%, 10%–50%, and 50%–100% viable tumor cells represent major, partial and poor pathologic response, respectively. ADC, adenocarcinoma; ASC, adenosquamous carcinoma; CNV, copy number variation; MSI, microsatellite instability; MSS, microsatellite stability; SCC, squamous cell carcinoma; SNP, single nucleotide polymorphism; TMB, tumor mutation burden.

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  Fig. 2 Genetic alterations enriched in Chinese, Caucasian patients or cervical adenocarcinoma (ADC). (A) Gene alterations significantly enriched in Chinese (blue) and Caucasian (red) patients were shown on the left and right respectively. (B) Gene mutations associated with cervical adenocarcinoma were shown in red. SCC, squamous cell carcinoma.

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  Fig. 3 Association of tumor mutation burden (TMB) with microsatellite instability in cervical cancer. Comparison of TMB levels in patients separated by microsatellite instability status (A) and histological types (B). ADC, adenocarcinoma; MSI, microsatellite instability; MSS, microsatellite stable; SCC, squamous cell carcinoma.

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  Fig. 4 Association of KEAP1 mutation and SOX2-PIK3CA co-amplification with high cervical cancer recurrence risk. Poor disease-free survival was observed in patients harbouring KEAP1 mutation (A) or SOX2-PIK3CA co-amplification (B). CI, confidence interval; HR, hazard ratio; mDFS, median disease-free survival; NR, not reported.

Reference

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