Skip to main content

Advertisement

SpringerLink
Log in

Assessment of significant procedures in multigene molecular detection for breast cancer in clinical laboratories: from variant detection to targeted therapy

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

In recent years, numerous novel targeted drugs against breast cancer have been developed because of the rapid progress in multigene molecular testing based on next-generation sequencing (NGS). However, it is a great challenge for clinicians to update the drug information timely, therefore necessitating that clinical laboratories provide adequate and comprehensive targeted drugs information to clinicians as a reference. The premise of providing this information is the accuracy of variant detection. Our study aimed to assess the entire process of variant detection, interpretation, and targeted therapy.

Methods

Laboratories were instructed to use routine methods for variant detection. The results were evaluated based on a predefined score system, and differences in variant interpretation were analyzed. Targeted drug information provided by laboratories was also summarized, and its accuracy and sufficiency were assessed.

Results

Overall, 90.1% (82/91) of the laboratories produced accurate results. 78.9% (15/19) of the errors were false positives or false negatives. Incorrect and insufficient drug information was mainly provided due to failure in timely database updating, inconsistencies with the detected mutations or given clinical information, and negligence during phase I clinical trials. To prioritize providing targeted drug information, laboratories collected data were based on different factors, including variant clinical significance, allele frequency, and variant positions in the signal pathway.

Conclusion

The variant detection capability was satisfactory, but the ability to provide accuracy and comprehensive targeted drug information should be urgently improved. Our study summarized a completed NGS-based multigene molecular detection pipeline, aiming to better inform precision treatment for breast cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Cardoso F, Harbeck N, Fallowfield L, Kyriakides S, Senkus E, on behalf of the EGWG. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23:vii9–11.

    Article  Google Scholar 

  2. Zardavas D, Baselga J, Piccart M. Emerging targeted agents in metastatic breast cancer. Nat Rev Clin Oncol. 2013;10:191–210.

    Article  CAS  Google Scholar 

  3. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.

    Article  CAS  Google Scholar 

  4. Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 2011;11:263–75.

    Article  CAS  Google Scholar 

  5. Amiri-Kordestani L, Wedam S, Zhang L, Tang S, Tilley A, Ibrahim A, et al. First FDA approval of neoadjuvant therapy for breast cancer: pertuzumab for the treatment of patients with HER2-positive breast cancer. Clin Cancer Res. 2014;20:5359–64.

    Article  CAS  Google Scholar 

  6. Ryan Q, Ibrahim A, Cohen MH, Johnson J, Ko CW, Sridhara R, et al. FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist. 2008;13:1114–9.

    Article  CAS  Google Scholar 

  7. Amiri-Kordestani L, Blumenthal GM, Xu QC, Zhang L, Tang SW, Ha L, et al. FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014;20:4436–41.

    Article  CAS  Google Scholar 

  8. Neratinib approved for HER2 + breast cancer. Cancer Discov. 2017;7:OF1.

  9. Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 2006;3:269–80.

    Article  CAS  Google Scholar 

  10. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92.

    Article  CAS  Google Scholar 

  11. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, et al. A functional genetic approach identifies the PI3 K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.

    Article  CAS  Google Scholar 

  12. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6:117–27.

    Article  CAS  Google Scholar 

  13. Andre F, Hurvitz S, Fasolo A, Tseng LM, Jerusalem G, Wilks S, et al. Molecular alterations and everolimus efficacy in human epidermal growth factor receptor 2-overexpressing metastatic breast cancers: combined exploratory biomarker analysis from BOLERO-1 and BOLERO-3. J Clin Oncol. 2016;34:2115–24.

    Article  Google Scholar 

  14. Juric D, Rodon J, Tabernero J, Janku F, Burris HA, Schellens JHM, et al. Phosphatidylinositol 3-kinase alpha-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: results from the first-in-human study. J Clin Oncol. 2018;36:1291–9.

    Article  CAS  Google Scholar 

  15. Guerin M, Rezai K, Isambert N, Campone M, Autret A, Pakradouni J, et al. PIKHER2: a phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer. Eur J Cancer. 2017;86:28–36.

    Article  CAS  Google Scholar 

  16. Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA, et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res. 2012;18:5816–28.

    Article  CAS  Google Scholar 

  17. Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3:224–37.

    Article  CAS  Google Scholar 

  18. Ma CX, Bose R, Gao F, Freedman RA, Telli ML, Kimmick G, et al. Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer. Clin Cancer Res. 2017;23:5687–95.

    Article  CAS  Google Scholar 

  19. Andre F, Bachelot T, Campone M, Dalenc F, Perez-Garcia JM, Hurvitz SA, et al. Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res. 2013;19:3693–702.

    Article  CAS  Google Scholar 

  20. Reis-Filho JS, Simpson PT, Turner NC, Lambros MB, Jones C, Mackay A, et al. FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas. Clin Cancer Res. 2006;12:6652–62.

    Article  CAS  Google Scholar 

  21. Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, et al. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res. 2012;72:2045–56.

    Article  CAS  Google Scholar 

  22. Guagnano V, Kauffmann A, Wohrle S, Stamm C, Ito M, Barys L, et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov. 2012;2:1118–33.

    Article  CAS  Google Scholar 

  23. Nkondjock A, Ghadirian P. Epidemiology of breast cancer among BRCA mutation carriers: an overview. Cancer Lett. 2004;205:1–8.

    Article  CAS  Google Scholar 

  24. Kim G, Ison G, McKee AE, Zhang H, Tang S, Gwise T, et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res. 2015;21:4257–61.

    Article  CAS  Google Scholar 

  25. Hoy SM. Talazoparib: first global approval. Drugs. 2018;78:1939–46.

    Article  Google Scholar 

  26. Grob TJ, Heilenkotter U, Geist S, Paluchowski P, Wilke C, Jaenicke F, et al. Rare oncogenic mutations of predictive markers for targeted therapy in triple-negative breast cancer. Breast Cancer Res Treat. 2012;134:561–7.

    Article  CAS  Google Scholar 

  27. Jelovac D, Beaver JA, Balukrishna S, Wong HY, Toro PV, Cimino-Mathews A, et al. A PIK3CA mutation detected in plasma from a patient with synchronous primary breast and lung cancers. Hum Pathol. 2014;45:880–3.

    Article  CAS  Google Scholar 

  28. Sun B, Ding L, Wu S, Meng X, Song S. Combined treatment with everolimus and fulvestrant reversed anti-HER2 resistance in a patient with refractory advanced breast cancer: a case report. Onco Targets Ther. 2016;9:3997–4003.

    Article  CAS  Google Scholar 

  29. den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat. 2016;37:564–9.

    Article  Google Scholar 

  30. Bandla S, Galimberti D, Kopp K, Anstead S, Zurenko C, Bonevich N, et al. Oncomine Knowledgebase Reporter: An information management system to link published evidence with cancer gene variants detected by multivariate tests. J Clin Oncol. 2016;34:e20667-e.

    Article  Google Scholar 

  31. Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: a Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19:4–23.

    Article  CAS  Google Scholar 

  32. Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. Genet Med. 2008;10:294–300.

    Article  CAS  Google Scholar 

  33. Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17:811–21.

    Article  CAS  Google Scholar 

  34. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 2008;68:9221–30.

    Article  CAS  Google Scholar 

  35. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724–34.

    Article  CAS  Google Scholar 

  36. Kim SB, Dent R, Im SA, Espie M, Blau S, Tan AR, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017;18:1360–72.

    Article  CAS  Google Scholar 

  37. Baselga J, Lewis Phillips GD, Verma S, Ro J, Huober J, Guardino AE, et al. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-positive metastatic breast cancer. Clin Cancer Res. 2016;22:3755–63.

    Article  CAS  Google Scholar 

  38. Wang L, Wheeler DA. Genomic sequencing for cancer diagnosis and therapy. Annu Rev Med. 2014;65:33–48.

    Article  CAS  Google Scholar 

  39. Chen K, Meric-Bernstam F, Zhao H, Zhang Q, Ezzeddine N, Tang LY, et al. Clinical actionability enhanced through deep targeted sequencing of solid tumors. Clin Chem. 2015;61:544–53.

    Article  CAS  Google Scholar 

  40. Baselga J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist. 2011;16(Suppl 1):12–9.

    Article  Google Scholar 

  41. National Comprehensive Cancer Network. (NCCN) Clinical Practice Guidelines in Oncology. Breast Cancer, Version 1. 2019. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 21 June 2019.

  42. Gao P, Zhang R, Li Z, Ding J, Xie J, Li J. Challenges of providing concordant interpretation of somatic variants in non-small cell lung cancer: a multicenter study. J Cancer. 2019;10:1814–24.

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by a grant from the Fund for Dongcheng Excellent Talents (Rui Zhang), Beijing Hospital Nova Project Grant BJ-2018-136 (Rui Zhang), and National Natural Science Foundation of China Grant 81772273 (Jinming Li).

Author information

Author notes

  1. Rui Zhang and Peng Gao have contributed equally to the work.

Authors and Affiliations

  1. National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People’s Republic of China

    Rui Zhang, Peng Gao, Jiansheng Ding, Ziyang Li & Jinming Li

  2. Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China

    Peng Gao, Jiansheng Ding, Ziyang Li & Jinming Li

  3. Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People’s Republic of China

    Rui Zhang, Peng Gao, Jiansheng Ding, Ziyang Li & Jinming Li

Authors
  1. Rui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiansheng Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ziyang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jinming Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Rui Zhang or Jinming Li.

Ethics declarations

Conflict of interest

The authors have stated that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. 1. Performance of the 91 participating laboratories.

The distribution of results is indicated by the columns of samples between the darkest vertical lines. A green box indicates a concordant result; a purple box indicates a false-negative result; a yellow box indicates a false-positive result; a red box indicates a mutation error; a pink box means a nomenclature error; and a gray box indicates no response was required, because a variant fell outside the specific detectable range. The variant allele frequencies reported are shown inside the boxes

Supplementary material 2 (XLSX 55 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, R., Gao, P., Ding, J. et al. Assessment of significant procedures in multigene molecular detection for breast cancer in clinical laboratories: from variant detection to targeted therapy. Breast Cancer 27, 111–121 (2020). https://doi.org/10.1007/s12282-019-01000-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-019-01000-2

Keywords

Search

Navigation