Featured Clinical Evidence

Selecting patients with non-small cell lung cancer (NSCLC) for cisplatin/pemetrexed treatment through ERCC1 protein expression analysis

In a recent study (see Abstract #1, below), GPS Cancer identified for the first time that ERCC1 protein expression can predict response to chemotherapy in patients with NSCLC. This finding resulted from a re-analysis of patient tumor samples from the TASTE clinical trial, which sought to determine the feasibility of customized therapy based on the mutation status of EGFR and expression levels of ERCC1 protein in patients with NSCLC. The phase 3 part of the TASTE trial was discontinued because assessment of ERCC1 protein expression by IHC proved unreliable.

Highlights

  • An undetectable level of ERCC1 protein, as assessed by GPS Cancer, is capable of predicting survival among patients treated with cisplatin (Figure). Patients with an undetectable level of ERCC1 protein expression had improved overall survival (statistically significant, p = .03) compared with patients whose tumors expressed ERCC1 protein. In this study, 14 of 15 cisplatin-treated patients who died during the TASTE trial had tumors that expressed the ERCC1 protein.

  • GPS Cancer simultaneously quantified other actionable protein biomarkers in patients’ tumor samples to inform selection of therapies. Protein biomarkers of response to pemetrexed were quantified. Patients with tumor expression of FRalpha >1639 amol/µg had longer overall survival than patients with FRalpha levels <1639 amol/µg. TYMS expression <150 amol/µg was similarly predictive of overall survival. ERCC1 clustered with the DNA damage markers TYMS and p16 in poor responders, while patients expressing FRalpha and E-cadherin had distinctly better survival outcomes. Multiplexed proteomics can quantitate ERCC1 simultaneously with other actionable protein biomarkers to inform selection of therapies.
  • Quantitative proteomic analysis confirmed immunohistochemistery (IHC) is not a reliable method to measure expression of ERCC1 protein. Mass spectrometry-based proteomic analysis found no detectable ERCC1 protein in 8/36 (22.2%) IHC-positive patients and 8/22 (19.3%) IHC-indeterminate patients. ERCC1 protein was detected in 71/88 (80.7%) IHC-negative patients (range: 36-137 amol/µg total tumor protein).

Findings from this study appeared in an oral presentation at the International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer in Vienna, Austria in December 2016: J. Soria et al. Proteomic Analysis of ERCC1 Predicts Benefit of Platinum Therapy in NSCLC: A Reevaluation of Samples From the TASTE Trial. Journal of Thoracic Oncology 12(1): S265-S266.

Abstracts

  1. Proteomic Analysis of ERCC1 Predicts Benefit of Platinum Therapy in NSCLC: A Reevaluation of Samples from the TASTE Trial. Soria, Jean-Charles et al. Journal of Thoracic Oncology, Volume 12, Issue 1, S265 - S266. 17th World Conference on Lung Cancer. December 2016.
  2. Clinical mass spectrometry-based proteomics unlocks personalized medicine potential from bone metastases. EORTC-NCI-AACR. December 2016.
  3. Mass spectrometry-based proteomic analysis may improve identification of patients sensitive to FGFR inhibitor therapy. Schwartz S, Tian Y, Fasani R, Diaz Delgado M, Hierro C, Rodon J, Sellappan S, Cecchi F, Hembrough T, Nuciforo P NantOmics, LLC, Rockville, MD; Vall d'Hebron Institute of Oncology, Barcelona, Spain; SABCS. December 2016.
  4. Domain-Specific c-Met Measurement by Quantitative Immunofluorescence and Mass Spectrometry in Non-Small Cell Lung Cancer. Toki M, Cecchi F, Hembrough T, Syrigos K, Rimm D. J Thorac Oncol. 2016 Nov;11(11S):S287. doi: 10.1016/j.jtho.2016.09.065.
  5. High-throughput identification of neoepitopes for the development of patient-specific cancer immunotherapies. Nguyen A, Sanborn JZ, Vaske CJ, Rabizadeh S, Niazi K, Soon-Shiong P, Benz SC. American Association for Cancer Research Annual Meeting. 2016 (abstr 4512).
  6. Targeted proteomic analysis for personalized treatment of muscle invasive bladder cancer. Cecchi F, Thyparambil S, Blackler A, Hembrough T, Rabizadeh S, Soon-Shiong P, Frierson H, Theodorescu D. American Association for Cancer Research Annual Meeting. 2016 (abstr 449).
  7. Targeted proteomic analysis of hepatocellular carcinoma and its histologic mimickers. Cecchi F, Ku N, Wang H, Blackler A, Hembrough T, Rabizadeh S, Soon-Shiong P, Huang J. American Association for Cancer Research Annual Meeting. 2016 (abstr 4935).
  8. Quantitative HER2 protein expression analysis in multiple cancer indications. Sellappan S, Schwartz S, Cecchi F, Blackler A, Soon-Shiong P, Rabizadeh S, Hembrough T. 14th International Congress on Targeted Anticancer Therapies. 2016 (abstr P5.2).
  9. KRAS gene amplification to define a distinct molecular subgroup of gastroesophageal adenocarcinoma. Henderson L, Xu P, O'Day E, Cecchi F, Blackler A, Liao W-L, Hembrough TA, Catenacci DVT. J Clin Oncol. 2016;34 (suppl 4S; abstr 74)
  10. Integrating whole genome sequencing data with RNAseq, pathway analysis, and quantitative proteomics to determine prognosis after standard adjuvant treatment with trastuzumab and chemotherapy in primary breast cancer patients. Benz SC, Rabizadeh S, Cecchi F, Beckman MW, Brucker SY, Hartmann A, Golovato J, Hembrough T, Janni W, Rack B, Sanborn JZ, Schneeweiss A, Vaske CJ, Soon-Shiong P, Fasching PA. San Antonio Breast Cancer Symposium 2015 (abstr P6-04-14)
  11. Quantitative HER family proteins assessment as prognostic and predictive biomarkers in the EGF30008 clinical trial. Nuciforo P, Thyparambil S, Galvá n P, Vilaro M, Jimenez J, Liao W-L, Cecchi F, Blackler A, Press MF, Gagnon R, Ellis C, Hembrough T, Johnston S, Prat A.  San Antonio Breast Cancer Symposium 2015 (abstr P3-07-08).
  12. Evaluation of MET using FISH, IHC, or mass spectrometry as a prognostic biomarker in patients with gastroesophageal cancer. Catenacci D, Shen J, Liao WL, Oliner K, Ang A, Loberg R, O'Day E, Xu P, Henderson L, Cecchi F, Burrows J, Hembrough T, Ruzzo A, Graziano F. European Cancer Congress 2015 (abstr 2397).
  13. Integrating whole exome sequencing data with RNAseq and quantitative proteomics to better inform clinical treatment decisions in patients with metastatic triple negative breast cancer. Soon-Shiong P, Rabizadeh S, Benz S, Cecchi F, Hembrough T, Mahen E, Burton K, Song C, Senecal F, Schmechel S, Pritchard C, Dorschner M, Blau S, Blau A. San Antonio Breast Cancer Symposium 2015 (abstr P6-05-08).
  14. Protein expression by genetic mutations identified in gene panels (hotspots) and efficacy of targeted treatments. Benz SC, Rabizadeh R, Sanborn JZ, Vaske CJ, Palmer GA, Soon-Shiong P, J Clin Oncol. 2015;33 (suppl; abstr 11005).
  15. Genomics, transcriptomics, and proteomics in the clinical setting: Integrating whole genome and RNA sequencing with quantitative proteomics to better inform clinical treatment selection. Rabizadeh S, Benz SC, Burrows J, Hembrough TA, Sanborn JZ, Vaske CJ, Soon-Shiong P. J Clin Oncol 33, 2015 (suppl; abstr 11093).
  16. An EMT-like gene expression profile differentiates helical from kinase domain PIK3CA mutations. Yau C, Garay J, Benz S, Gray J, Park B, Benz CC. Cancer Res. 201575 (suppl; abstr 1084).
  17. Whole genome sequencing and quantitative proteomics reveal HPV integration and HER2 overexpression in a patient with cervical cancer: Comprehensive omics analysis driving clinical treatment decisions. Benz S, Sanborn JZ, Hensley NS, Hembrough T, Vaske CJ, Burrows J, Rabizadeh S, Royston I, Soon-Shiong P. AACR Precision Medicine Series. 2015; abstr.
  18. Proteomic analysis of primary and metastatic breast cancers and expression of the folate receptor as a potential drug target. Hembrough TA, Cecchi F, Blackler A, Thyparambil SP, Burrows J, O'Shaughnessy J. J Clin Oncol 33, 2015 (suppl; abstr 1045).
  19. Quantitative measurement of HER2 levels by multiplexed mass spectrometry to predict survival in gastric cancer patients treated with trastuzumab. Ock C-Y, An E, Oh D-Y, Kim T-Y, Lee K-H, Han S-W, Im S-A, Kim T-Y, Liao W-L, Cecchi F, Blackler A, Thyparambil SP, Hoos WA, Kim WH, Burrows J, Hembrough TA, Bang Y-J. J Clin Oncol 2015; 33 (suppl; abstr 4050).
  20. HER2 quantification by mass spectrometry compared to IHC or ISH in predicting clinical benefit from anti-HER2 therapy in HER2-positive breast cancer (BC).Nuciforo P, Aura C, Thyparambil SP, Vilaro M, Garrido-Castro AC, Peg V, Jimenez J, Hoos WA, Burrows J, Hembrough TA, Perez-Garcia JM, Cortes J, Scaltriti M. J Clin Oncol 33, 2015 (suppl; abstr 605).
  21. Clinical implication of mass-spectrometry-based selected reaction monitoring (SRM) assay in non-small cell lung cancer (NSCLC) patients exhibiting ALK gene rearrangement. An HJ, An E, Liao W-L, Kang JH, Burrows J, Hembrough TA, Kim T-J. J Clin Oncol 2015; 33 (suppl; abstr e22145).
  22. Quantitative Mass Spectrometry Proteomics Identifies FRalpha and GARFT as Predictive Biomarkers in NSCLC Patients Treated With Pemetrexed.  Alshehri AA, An E, Cecchi F, Hembrough T, Ma PC,  Smolkin M, Wen S, Monga M. 16th World Conference on Lung Cancer. 2015 (abstr 106).
  23. Clinical Survey of actionable proteins in multiple indications using multiplex mass spectrometry.  Cecchi F, Blackler A, Jordan H, Stocum M, Darfler M, Hembrough T, Burrows J. Ann Oncol 2015;26 (suppl 2).
  24. ChemoPlex SRM assay predicts response to specific chemotherapeutic agents in NSCLC.  An E, Kim T-J, Monga M, Bengali K, Drilea A, Reilly J, Darfler M, Burrows J, Hembrough T. Cancer Research 2015;75 (suppl; abstr 566).
  25. Clinical Survey of 19 actionable proteins in multiple indications using multiplex mass spectrometry. Cecchi F, Blackler A, Jordan H, Darfler M, Hembrough T, Stocum M, Burrows J. Cancer Research 2015;75 (suppl; abstr 3395).
  26. Development of a mass spectrometry based antibody-drug conjugate biomarker panel. Blackler A, Liao W-L, Thyparambil S, An E, Cecchi F, Darfler M, Hembrough T, Burrows J. Cancer Research 2015;75 (suppl; abstr 3398).
  27. Development and clinical validation of a quantitative mass spectrometric assay for immuno-oncology targets in FFPE samples. Thyparambil SP, Cecchi F, An E, Liao W-L, Burrows J, Hembrough T, Catenacci D. Cancer Research 2015;75 (suppl; abstr 3398).
  28. Her2 expression in gastroesophageal cancer (GEC) FFPE tissue using mass spectrometry (MS) and correlation with HER2 gene amplification. Catenacci D, Zhao L, Whitcomb E, Henderson L, O'Day E, Xu P, Xiao S-Y, Lee SM, Liao W-L, Thyparambil SP, Uzzell J, Darfler M, Krizman D, Burrows J, Hembrough TA; J Clin Oncol 2015;33 (suppl 3; abstr 82).
  29. Correlation of high levels of HER2 measured by multiplex mass spectrometry with increased overall survival in patients treated with anti-HER2-based therapy. Nuciforo P, Thyparambil SP, Garrido-Castro AC, Peg V, Prudkin L, Jimenez J, Hoos WA, Burrows J, Hembrough TA, Perez-Garcia JM, Cortes J, Scaltriti M. J Clin Oncol 2014;32:5s (suppl; abstr 649).
  30. Escape of EML4-ALK NSCLC to early phase precision therapy through TGFβ2-HOX-bioenergetics reprogramming. Yin L, Zhang W, Shi I, Feng Y, Choi H, Bagai RK, Makishima H, Lanigan C, Cicenia J, Gildea T, Liao W-L, Hembrough TA, Burrows J, Tubbs RR, Lindner D, Almeida F, Maciejewski JP, Ma PC. J Clin Oncol 2014;32 (suppl; abstr e19044).
  31. A comprehensive analysis of molecular profiles across over 10,000 tumor and germ-line exomes across more than 20 tumor types: Novel mechanisms and targets for clinical treatment.  Rabizadeh S, Benz SC, Sanborn JZ, Vaske CJ, Soon-Shiong P. J Clin Oncol 2014;32 (suppl; abstr 11031).
  32. Multi-omic profiling to predict response to gemcitabine/ carboplatin (GC) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer using a pathway-based approach. Vinayak S, Benz SC, Vaske CJ, Telli ML, Ford JM. Cancer Res 2014;24 (suppl; abstr 2826).
  33. Differential pathway activation associated with domain-specific PIK3CA mutations. Yau C, Benz S, Vaske C, Ng S, Stuart J, Benz CC. Cancer Res 2014;74 (suppl; abstr 4165)