Genetics and Genomics

Multi-omic molecular comparison of primary versus metastatic pancreatic tumours

Abstract

Background

Molecular profiling is increasingly used to match patients with metastatic cancer to targeted therapies, but obtaining a high-quality biopsy specimen from metastatic sites can be difficult.

Methods

Patient samples were received by Perthera to coordinate genomic, proteomic and/or phosphoproteomic testing, using a specimen from either the primary tumour or a metastatic site. The relative frequencies were compared across specimen sites to assess the potential limitations of using a primary tumour sample for clinical decision support.

Results

No significant differences were identified at the gene or pathway level when comparing genomic alterations between primary and metastatic lesions. Site-specific trends towards enrichment of MYC amplification in liver lesions, STK11 mutations in lung lesions and ATM and ARID2 mutations in abdominal lesions were seen, but were not statistically significant after false-discovery rate correction. Comparative analyses of proteomic results revealed significantly elevated expression of ERCC1 and TOP1 in metastatic lesions.

Conclusions

Tumour tissue limitations remain a barrier to precision oncology efforts, and these real-world data suggest that performing molecular testing on a primary tumour specimen could be considered in patients with pancreatic adenocarcinoma who do not have adequate tissue readily available from a metastatic site.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA: a Cancer J. Clin. 68, 7–30 (2018).

  2. 2.

    Smith, B. D., Smith, G. L., Hurria, A., Hortobagyi, G. N. & Buchholz, T. A. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J. Clin. Oncol. 27, 2758–2765 (2009).

  3. 3.

    Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M. & Matrisian, L. M. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).

  4. 4.

    Neoptolemos, J. P., Palmer, D. H., Ghaneh, P., Psarelli, E. E., Valle, J. W., Halloran, C. M. et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 389, 1011–1024 (2017).

  5. 5.

    Sarnecka, A. K., Zagozda, M. & Durlik, M. An Overview of Genetic Changes and Risk of Pancreatic Ductal Adenocarcinoma. J. Cancer. 7, 2045–2051 (2016).

  6. 6.

    Von Hoff, D. D., Ervin, T., Arena, F. P., Chiorean, E. G., Infante, J., Moore, M. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).

  7. 7.

    Conroy, T., Desseigne, F., Ychou, M., Bouche, O., Guimbaud, R., Becouarn, Y. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011).

  8. 8.

    Waddell, N., Pajic, M., Patch, A. M., Chang, D. K., Kassahn, K. S., Bailey, P. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).

  9. 9.

    Ramaswamy, S., Ross, K. N., Lander, E. S. & Golub, T. R. A molecular signature of metastasis in primary solid tumors. Nature Genet. 33, 49–54 (2003).

  10. 10.

    Gerlinger, M., Rowan, A. J., Horswell, S., Math, M., Larkin, J., Endesfelder, D. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

  11. 11.

    Bertucci, F., Finetti, P., Guille, A., Adelaide, J., Garnier, S., Carbuccia, N. et al. Comparative genomic analysis of primary tumors and metastases in breast cancer. Oncotarget. 7, 27208–27219 (2016).

  12. 12.

    Van Poznak, C., Somerfield, M. R., Bast, R. C., Cristofanilli, M., Goetz, M. P., Gonzalez-Angulo, A. M. et al. Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 33, 2695–2704 (2015).

  13. 13.

    Van den Broeck, A., Sergeant, G., Ectors, N., Van Steenbergen, W., Aerts, R. & Topal, B. Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma. Eur. J. Surg. Oncol. 35, 600–604 (2009).

  14. 14.

    Campbell, P. J., Yachida, S., Mudie, L. J., Stephens, P. J., Pleasance, E. D., Stebbings, L. A. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 467, 1109–1113 (2010).

  15. 15.

    Yachida, S., Jones, S., Bozic, I., Antal, T., Leary, R., Fu, B. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 467, 1114–1117 (2010).

  16. 16.

    Choueiri, M. B., Shen, J. P., Gross, A. M., Huang, J. K., Ideker, T. & Fanta, P. ERCC1 and TS expression as prognostic and predictive biomarkers in metastatic colon cancer. PloS ONE. 10, e0126898 (2015).

  17. 17.

    Braun, M. S., Richman, S. D., Quirke, P., Daly, C., Adlard, J. W., Elliott, F. et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J. Clin. Oncol. 26, 2690–2698 (2008).

  18. 18.

    Fan, P., Liu, L., Yin, Y., Zhao, Z., Zhang, Y., Amponsah, P. S. et al. MicroRNA-101-3p reverses gemcitabine resistance by inhibition of ribonucleotide reductase M1 in pancreatic cancer. Cancer Lett. 373, 130–137 (2016).

  19. 19.

    Gao, S., Zhao, X., Lin, B., Hu, Z., Yan, L. & Gao, J. Clinical implications of REST and TUBB3 in ovarian cancer and its relationship to paclitaxel resistance. Tumour Biol. 33, 1759–1765 (2012).

  20. 20.

    Witkiewicz, A. K., McMillan, E. A., Balaji, U., Baek, G., Lin, W. C., Mansour, J. et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat. Commun. 6, 6744 (2015).

  21. 21.

    Momcilovic, M. & Shackelford, D. B. Targeting LKB1 in cancer-exposing and exploiting vulnerabilities. Br. J. Cancer 113, 574–584 (2015).

  22. 22.

    Hodges, C., Kirkland, J. G., & Crabtree, G. R. The many roles of BAF (mSWI/SNF) and PBAF complexes in cancer. Cold Spring Harb. Perspect. Med. 6, 1–25 (2016).

  23. 23.

    Lange, J., Pan, J., Cole, F., Thelen, M. P., Jasin, M. & Keeney, S. ATM controls meiotic double-strand-break formation. Nature. 479, 237–240 (2011).

  24. 24.

    Pishvaian, M. J., Bender, R. J., Halverson, D., Rahib, L., Hendifar, A. E., Mikhail, S. et al. Molecular profiling of patients with pancreatic cancer: initial results from the know your tumor initiative. Clin. Cancer Res. 24, 5018–5027 (2018).

  25. 25.

    Macfarlane, R., Seal, M., Speers, C., Woods, R., Masoudi, H., Aparicio, S. et al. Molecular alterations between the primary breast cancer and the subsequent locoregional/metastatic tumor. Oncologist. 17, 172–178 (2012).

  26. 26.

    El-Deiry, W. S., Vijayvergia, N., Xiu, J., Scicchitano, A., Lim, B., Yee, N. S. et al. Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites. Cancer Biol. Ther. 16, 1726–1737 (2015).

  27. 27.

    Barrett, M. T., Deiotte, R., Lenkiewicz, E., Malasi, S., Holley, T., Evers, L. et al. Clinical study of genomic drivers in pancreatic ductal adenocarcinoma. Br. J. Cancer 117, 572–582 (2017).

  28. 28.

    Makohon-Moore, A. P., Zhang, M., Reiter, J. G., Bozic, I., Allen, B., Kundu, D. et al. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat. Genet. 49, 358–366 (2017).

  29. 29.

    McDonald, O. G., Li, X., Saunders, T., Tryggvadottir, R., Mentch, S. J., Warmoes, M. O. et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat. Genet. 49, 367–376 (2017).

  30. 30.

    Reiter, J. G., Makohon-Moore, A. P., Gerold, J. M., Heyde, A., Attiyeh, M. A., Kohutek, Z. A. et al. Minimal functional driver gene heterogeneity among untreated metastases. Science. 361, 1033–1037 (2018).

  31. 31.

    Iacobuzio-Donahue, C. A. Genetic evolution of pancreatic cancer: lessons learnt from the pancreatic cancer genome sequencing project. Gut. 61, 1085–1094 (2012).

  32. 32.

    Hoos, W. A., James, P. M., Rahib, L., Talley, A. W., Fleshman, J. M. & Matrisian, L. M. Pancreatic cancer clinical trials and accrual in the United States. J. Clin. Oncol. 31, 3432–3438 (2013).

Download references

Acknowledgements

We thank the Pancreatic Cancer Action Network for acquisition of tissue samples.

Author information

G.B., E.M.B. and R.J.B. wrote the paper with support from J.R.B., D.S., S.M., V.M.C., E.P. and M.J.P. The study was designed and developed by M.J.P. and E.P. with support from V.J.P., A.E.H., D.H. and S.M. Tissue samples and funding were supported by L.M.M. and L.R.

Correspondence to Michael J. Pishvaian.

Ethics declarations

Competing interests

E.M.B., J.R.B., S.M., E.P. and M.J.P. all have equity and employment with Perthera. L.M.M. and L.R. have equity and employment at the Pancreatic Cancer Action Network. All other authors declare that they have no conflict of interest.

Ethics approval and consent to participate

The study protocol, amendments and informed consent forms were approved by the New England Institutional Review Board (Protocol # PCT-01-012). Investigators obtained informed consent from each participant or participant’s guardian prior to enrolment. The research was conducted in accordance with recognised ethical guidelines, including the Declaration of Helsinki, CIOMS, Belmont Report and U.S. Common Rule, as described during training in Good Clinical Practice guidelines (CITI Training).

Funding

No relevant funding was used for this project.

Data availability

Archival study data used to produce the results reported in this article can be found at Perthera and the Pancreatic Cancer Action Network’s Know Your Tumor program.

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Brar, G., Blais, E.M., Joseph Bender, R. et al. Multi-omic molecular comparison of primary versus metastatic pancreatic tumours. Br J Cancer 121, 264–270 (2019). https://doi.org/10.1038/s41416-019-0507-5

Download citation

Further reading