Tumor mutational burden is not predictive of cytotoxic chemotherapy response

Mina Nikanjam, Paul Riviere, Aaron Goodman, Donald A Barkauskas, Garrett Frampton, Razelle Kurzrock, Mina Nikanjam, Paul Riviere, Aaron Goodman, Donald A Barkauskas, Garrett Frampton, Razelle Kurzrock

Abstract

Background: High tumor mutational burden (TMB) predicts checkpoint blockade responsiveness, although the association with outcomes may be nuanced in certain tissue contexts. The correlation between TMB and cytotoxic chemotherapy sensitivity is unknown. This study evaluated the relationship between TMB and outcome in patients with solid tumors receiving cytotoxic chemotherapy.

Methods: University of California San Diego patients who received cytotoxic chemotherapy within one year after biopsy for TMB evaluation were included in a retrospective analysis. Physician notes and imaging reports in the electronic medical record were reviewed to determine clinical benefit and progression-free survival (PFS).

Results: Among 1526 patients with TMB availability, there were 294 eligible patients who received chemotherapy. There were no significant differences in TMB between those with stable disease ≥6 months/partial response/complete response versus others (t-test, p = .22). There were no significant differences in PFS for patients with TMB <10 vs. TMB ≥10 mutations/Mb (log-rank test, median and 95% CI: 6.0 (4.8-7.4) vs. 5.4 (4.3-6.6) months; p = .21). Nor were there significant differences in PFS for patients with a TMB <10 vs. TMB ≥10 mutations/mb for breast (p = .07), lung (p = .47), or gastrointestinal cancer (p = .53).

Conclusions: In summary, TMB was not predictive of stable disease ≥6 months/partial response/complete response or PFS in patients receiving cytotoxic chemotherapy.

Trials registration: NCT02478931.

Keywords: Tumor mutational burden; biomarker; cytotoxic chemotherapy; oncology.

© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.

Figures

Figure 1.
Figure 1.
Consort diagram for study.
Figure 2.
Figure 2.
Tumor mutational burden vs. SD≥6 months/PR/CR. Data represent the median and 25–75% interquartile range for tumor mutational burden. Patients with SD≥6 months/PR/CR after chemotherapy had similar tumor mutational burden to those with progression disease (PD) or SDp = .22). Patients with stable disease who were censored prior to 6 months of evaluation were excluded from the analysis.
Figure 3.
Figure 3.
Kaplan Meier survival analysis. Progression-free survival for patients with tumor mutational burden of 10 or greater is similar to those with TMB less than 10 (p = .21).

References

    1. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–5. doi:10.1126/science.aaa1348.
    1. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS.. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189–2199. doi:10.1056/NEJMoa1406498.
    1. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, Stephens PJ, Daniels GA, Kurzrock R. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598–2608. doi:10.1158/1535-7163.MCT-17-0386.
    1. Khagi Y, Kurzrock R, Patel SP. Next generation predictive biomarkers for immune checkpoint inhibition. Cancer Metastasis Rev. 2017;36:179–190. doi:10.1007/s10555-016-9652-y.
    1. Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, Peters S. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 2019;30:44–56. doi:10.1093/annonc/mdy495.
    1. Fancello L, Gandini S, Pelicci PG, Mazzarella L. Tumor mutational burden quantification from targeted gene panels: major advancements and challenges. J Immunother Cancer. 2019;7:183. doi:10.1186/s40425-019-0647-4.
    1. Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, Barron DA, Zehir A, Jordan EJ, Omuro A. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–206. doi:10.1038/s41588-018-0312-8.
    1. Zhu J, Zhang T, Li J, Lin J, Liang W, Huang W, Wan N, Jiang J. Association Between Tumor Mutation Burden (TMB) and outcomes of cancer patients treated with PD-1/PD-L1 inhibitions: a meta-analysis. Front Pharmacol. 2019;10:673. doi:10.3389/fphar.2019.00673.
    1. Goodman AM, Sokol ES, Frampton GM, Lippman SM, Kurzrock R. Microsatellite-stable tumors with high mutational burden benefit from immunotherapy. Cancer Immunol Res. 2019;7:1570–1573. doi:10.1158/2326-6066.CIR-19-0149.
    1. Nikanjam M, Arguello D, Gatalica Z, Swensen J, Barkauskas DA, Kurzrock R. Relationship between protein biomarkers of chemotherapy response and microsatellite status, tumor mutational burden and PD-L1 expression in cancer patients. Int J Cancer. 2020;146(11):3087–3097.
    1. Friboulet L, Olaussen KA, Pignon JP, Shepherd FA, Tsao MS, Graziano S, Kratzke R, Douillard J-Y, Seymour L, Pirker R. ERCC1 isoform expression and DNA repair in non-small-cell lung cancer. N Engl J Med. 2013;368:1101–1110. doi:10.1056/NEJMoa1214271.
    1. Choi M, Kipps T, Kurzrock R. ATM mutations in cancer: therapeutic implications. Mol Cancer Ther. 2016;15:1781–1791. doi:10.1158/1535-7163.MCT-15-0945.
    1. Weaver BA, Silk AD, Montagna C, Verdier-Pinard P, Cleveland DW. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell. 2007;11:25–36. doi:10.1016/j.ccr.2006.12.003.
    1. Holland AJ, Cleveland DW. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol. 2009;10:478–487. doi:10.1038/nrm2718.
    1. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, Schnall-Levin M, White J, Sanford EM, An P. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31(11):1023–1031. doi:10.1038/nbt.2696.
    1. Johnson DB, Frampton GM, Rioth MJ, Yusko E, Xu Y, Guo X, Ennis RC, Fabrizio D, Chalmers ZR, Greenbowe J, et al. Targeted next generation sequencing identifies markers of response to PD-1 blockade. Cancer Immunol Res. 2016;4(11):959–967. doi:10.1158/2326-6066.CIR-16-0143.
    1. Hetland TE, Hellesylt E, Florenes VA, Trope C, Davidson B, Kaern J. Class III beta-tubulin expression in advanced-stage serous ovarian carcinoma effusions is associated with poor survival and primary chemoresistance. Hum Pathol. 2011;42:1019–1026. doi:10.1016/j.humpath.2010.10.025.
    1. Mozzetti S, Ferlini C, Concolino P, Filippetti F, Raspaglio G, Prislei S, Gallo D, Martinelli E, Ranelletti FO, Ferrandina G. Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients. Clin Cancer Res. 2005;11:298–305.
    1. Ploussard G, Terry S, Maille P, Allory Y, Sirab N, Kheuang L, Soyeux P, Nicolaiew N, Coppolani E, Paule B. Class III beta-tubulin expression predicts prostate tumor aggressiveness and patient response to docetaxel-based chemotherapy. Cancer Res. 2010;70:9253–9264. doi:10.1158/0008-5472.CAN-10-1447.
    1. Braun MS, Richman SD, Quirke P, Daly C, Adlard JW, Elliott F, Barrett JH, Selby P, Meade AM, Stephens RJ. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol. 2008;26(16):2690–2698. doi:10.1200/JCO.2007.15.5580.
    1. Rodrigo RS, Nathalie A, Elodie T, Gonzalo GA, Philippe T, Francoise D, Julien D, Angela C, Bérénice B, Jean-Yves B. Topoisomerase II-alpha protein expression and histological response following doxorubicin-based induction chemotherapy predict survival of locally advanced soft tissues sarcomas. Eur J Cancer. 2011;47:1319–1327. doi:10.1016/j.ejca.2011.02.010.
    1. Sun JM, Ahn JS, Jung SH, Sun J, Ha SY, Han J, Park K, Ahn M-J. Pemetrexed plus cisplatin versus gemcitabine plus cisplatin according to thymidylate synthase expression in nonsquamous non-small-cell lung cancer: a biomarker-stratified randomized phase II trial. J Clin Oncol. 2015;33:2450–2456. doi:10.1200/JCO.2014.59.9324.
    1. Qiu LX, Tang QY, Bai JL, Qian XP, Li RT, Liu BR, Zheng M-H. Predictive value of thymidylate synthase expression in advanced colorectal cancer patients receiving fluoropyrimidine-based chemotherapy: evidence from 24 studies. Int J Cancer. 2008;123:2384–2389. doi:10.1002/ijc.23822.
    1. Park SE, Park K, Lee E, Kim J-Y, Ahn JS, Im Y-H, Lee C, Jung H, Cho SY, Park W-Y. Clinical implication of tumor mutational burden in patients with HER2-positive refractory metastatic breast cancer. Oncoimmunology. 2018;7:e1466768. doi:10.1080/2162402X.2018.1466768.
    1. Pai S, Carneiro B, Kalyan A, Costa R, Helenowski I, Radmeaker A, et al. Correlation of tumor mutation burden and chemotherapy outcomes in colorectal cancer. American Association of Cancer Research. Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC.
    1. Nikanjam M, Arguello D, Gatalica Z, Swensen J, Barkauskas DA, Kurzrock R. Relationship between protein biomarkers of chemotherapy response and microsatellite status, tumor mutational burden and PD-L1 expression in cancer patients. Int J Cancer. 2020;146:3087–3097. doi:10.1002/ijc.32661.

Source: PubMed

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