Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA
Mitsukuni Suenaga , Shu Cao , Sebastian Stintzing , Wu Zhang , Dongyun Yang , Yan Ning , Satoshi Okazaki , Martin D. Berger , Yuji Miyamoto , Marta Schirripa , Roel Gopez Jr., Elizabeth Melendez , Shivani Soni , Afsaneh Barzi , Toshiharu Yamaguchi , Volker Heinemann , Heinz-Josef Lenz
Background: EGFR signaling blockade increases CCL5 expression, which attracts with tumor-infiltrating leukocytes regulating either the host-derived anti-tumor immunity or tumor progression. We tested whether genetic polymorphisms in the CCL5/CCR5 axis could predict efficacy of cetuximab (CET)-based first-line treatment in metastatic colorectal cancer (mCRC) patients (pts). Methods: Genomic DNA was extracted from 491 samples of two different cohorts with KRAS wild-type mCRC in the FIRE-3 study: an evaluation cohort of 244 pts receiving CET plus FOLFIRI (median age 64 yrs; median follow-up 34.1 mos); and a control cohort of 247 pts receiving bevacizumab plus FOLFIRI (median age 65 yrs; median follow-up 39.4 mos); Single nucleotide polymorphisms (SNPs) of CCL5 and CCR5 genes were analyzed by PCR-based direct sequencing. Results: Pts in the evaluation cohort with any CCL5 rs2280789 G allele had shorter OS compared to those with the A/A variant (19.9 vs. 33.4 mos, HR 1.56, 95%CI: 1.05–2.30, P= 0.024), which was confirmed in multivariable analysis (HR 1.64, P= 0.015). Pts carrying any CCR5 rs1799988 T allele had a trend lower response rate than those with the C/C variant (68 vs. 81%, P= 0.078). Statistically significant differences in efficacy were shown between the groups consisting SNPs and tumor location (Table). The findings were not confirmed in the control cohort. Conclusions: Genetic variants of CCL5 and CCR5 SNPs may predict outcomes in mCRC pts receiving CET-based first-line treatment depending on tumor location.
Response rate (%) | P value | Median PFS (mos) | HR | P value | Median OS (mos) | HR | P value | |
---|---|---|---|---|---|---|---|---|
All KRAS wt | ||||||||
Location –CCR5 | < 0.001 | < 0.001 | < 0.001 | |||||
La– C/C | 91 | 10.6 | 1 | 38.5 | 1 | |||
L – Any T | 66 | 10.0 | 1.30 | 30.6 | 1.32 | |||
Rb– T/T | 92 | 9.0 | 1.56 | 27.1 | 1.66 | |||
R – Any C | 48 | 6.5 | 3.00 | 15.8 | 3.99 | |||
–CCL5 | 0.28 | 0.001 | < 0.001 | |||||
L – A/A | 74 | 10.5 | 1 | 38.3 | 1 | |||
L – Any G | 71 | 10.0 | 1.17 | 21.7 | 1.43 | |||
R – A/A | 68 | 7.8 | 1.95 | 21.9 | 2.45 | |||
R – Any G | 44 | 3.9 | 2.13 | 18.3 | 3.33 | |||
All RAS wt | ||||||||
Location –CCR5 | 0.002 | < 0.001 | < 0.001 | |||||
L – C/C | 92 | 11.5 | 1 | 42.8 | 1 | |||
L – Any T | 75 | 10.5 | 1.13 | 38.7 | 1.13 | |||
R – T/T | 88 | 12.2 | 1.41 | 27.1 | 1.51 | |||
R – Any C | 47 | 6.5 | 3.12 | 11.7 | 4.73 | |||
–CCL5 | 0.059 | < 0.001 | < 0.001 | |||||
L – A/A | 82 | 10.9 | 1 | 41.2 | 1 | |||
L – Any G | 73 | 10.0 | 1.13 | 20.3 | 1.79 | |||
R – A/A | 65 | 7.3 | 2.23 | 16.5 | 3.04 | |||
R – Any G | 40 | 3.9 | 2.10 | 18.3 | 5.40 |
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