Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 142 No. 1718 (2012)

Targeted therapies in breast cancer

  • Andreas Wicki
  • Christoph Rochlitz
DOI
https://doi.org/10.4414/smw.2012.13550
Cite this as:
Swiss Med Wkly. 2012;142:w13550
Published
22.04.2012

Abstract

Targeted therapies have improved cure rates and prolonged survival in metastasised breast cancer. The most important new molecular targets in breast cancer therapy are epidermal growth factor receptor (ErbB) family signalling, DNA repair pathways and angiogenesis. Blocking ErbB2 signalling with anti-ErbB2 antibodies or ErbB2 kinase inhibitors is effective in both the adjuvant and the palliative treatment of ErbB2 positive breast cancer. Poly-ADP-ribose polymerase (PARP) inhibitors lead to synthetic lethality in double strand repair deficient tumours. Anti-VEGF antibodies reduce tumour-induced angiogenesis and prolong progression-free survival in breast cancer. The use of both PARP inhibitors and antiangiogenic therapy is currently hampered by a lack of predictive biomarkers. In contrast, predictive markers are available for ErbB family signalling.

This review is intended to give a concise summary of recent developments in the therapy of breast cancer with a focus on new, targeted therapies.

References

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
  2. Hammond ME, Hayes DF, Wolff AC. Clinical notice for American Society of Clinical Oncology – College of American Pathologists Guideline Recommendations on ER/PgR and HER2 testing in breast cancer. J Clin Oncol. 2011;29:e458.
  3. Wolff AC, M. Elizabeth H. Hammond, Jared N. Schwartz, et al. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2006;25:118–45.
  4. Slamon DJ, Leyland-Jones B, Shak S, 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.
  5. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.
  6. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84.
  7. Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. 2010;28:92–8.
  8. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:719–26.
  9. Nagata Y, Lan KH, Zhou X 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.
  10. Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.
  11. Burris HA, Rugo HS, Vukelja SJ et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29:398–405.
  12. Chandarlapaty S, Sawai A, Scaltriti M et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011;19:58–71.
  13. Morrow PK, Wulf GM, Ensor J et al. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol. 2011;29:3126–32.
  14. Hsieh AC, Costa M, Zollo O et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell. 2010;17:249–61.
  15. von Minckwitz G, du Bois A, Schmidt M et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009;27:1999–2006.
  16. von Minckwitz G, Schwedler K, Schmidt M et al. Trastuzumab beyond progression: Overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011;47:2273–81.
  17. Koch KM, Reddy NJ, Cohen RB et al. Effects of food on the relative bioavailability of lapatinib in cancer patients. J Clin Oncol. 2009;27:1191–6.
  18. Tannock IF. Effects of food on bioavailability of lapatinib: useful data, wrong conclusion. J Clin Oncol. 2009;27:e42; author reply e43.
  19. Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–43.
  20. Lin NU, Eierman W, Greil R, et al. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J Neurooncol. 2011.
  21. Finn RS, Press MF, Dering J, et al. Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer. J Clin Oncol. 2009;27:3908–15.
  22. Johnston S, Pippen JJ, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27:5538–46.
  23. Di Leo A, Gomez HL, Aziz Z, et al. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol. 2008;26:5544–52.
  24. Blackwell KL, Burstein HJ, Storniolo AM et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124–30.
  25. Kaufman B, Trudeau M, Awada A, et al. Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study. Lancet Oncol. 2009;10:581–8.
  26. Blackwell KL, Pegram MD, Tan-Chiu E, et al. Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. Ann Oncol. 2009;20:1026–31.
  27. Boussen H, Cristofanilli M, Zaks T, DeSilvio M, Salazar V, Spector N. Phase II study to evaluate the efficacy and safety of neoadjuvant lapatinib plus paclitaxel in patients with inflammatory breast cancer. J Clin Oncol. 2010;28:3248–55.
  28. von Minckwitz G, Eidtmann H, Loibl S, et al. Integrating bevacizumab, everolimus, and lapatinib into current neoadjuvant chemotherapy regimen for primary breast cancer. Safety results of the GeparQuinto trial. Ann Oncol. 2011;22:301–6.
  29. Dave B, Migliaccio I, Gutierrez MC, et al. Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol. 2011;29:166–73.
  30. Wilson TR, Lee DY, Berry L, Shames DS, Settleman J. Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers. Cancer Cell. 2011;20:158–72.
  31. Baselga J, Gelmon KA, Verma S et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010;28:1138–44.
  32. Gianni L, Pienkowski T, Im YH, et al. Neoadjuvant pertuzumab and trastuzumab: antitumor safety analysis of a randomized phase II study (‘Neosphere’). SABCS. 2010; abstr S3-2.
  33. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109–19.
  34. Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28:1301–7.
  35. Modi S, Stopeck A, Linden H, et al. HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res. 2011;17:5132–9.
  36. Arteaga CL. Why is this effective HSP90 inhibitor not being developed in HER2+ breast cancer? Clin Cancer Res. 2011;17:4919–21.
  37. Nielsen TO, Hsu FD, Jensen K et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10:5367–74.
  38. Cristofanilli M SRVV, et al. Exploratory subset analysis according to prior endocrine treatment of two randomized phase II trials comparing gefitinib with placebo in combination with tamoxifen or anastrozole in hormone receptor positive metastatic breast cancer. J Clin Oncol. 2009;27:suppl; abstr 1014.
  39. Teng YH, Tan WJ, Thike AA, et al. Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy. Breast Cancer Res. 2011;13:R35.
  40. Chow LSY JJ, Baselga J, et al. Phase III study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. Breast Cancer Res Treat. 2006;97:suppl; abstr 6091.
  41. Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009;27:2630–7.
  42. Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New Engl J Med. 2012;366:520–9.
  43. Tryfonopoulos D, Walsh S, Collins DM, et al. Src: a potential target for the treatment of triple-negative breast cancer. Ann Oncol. 2011;22:2234–40.
  44. Herold CI, Chadaram V, Peterson BL, et al. Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing. Clin Cancer Res. 2011;17:6061–70.
  45. Campone M, Bondarenko I, Brincat S, et al. Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy. Ann Oncol. 2011 AOP doi:10.1093/annonc/mdr261.
  46. Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings. Mol Oncol. 2011;5:387–93.
  47. Turner N, Tutt A, Ashworth A. Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer. 2004;4:814–9.
  48. Stefansson OA, Jonasson JG, Olafsdottir K, et al. CpG island hypermethylation of BRCA1 and loss of pRb as co-occurring events in basal/triple-negative breast cancer. Epigenetics. 2011;6:638–49.
  49. Johnson N, Li YC, Walton ZE, et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat Med. 2011;17:875–82.
  50. O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205–14.
  51. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer. J Clin Oncol. 2011;29:suppl; abstr 1007.
  52. Guha M. PARP inhibitors stumble in breast cancer. Nat Biotechnol. 2011;29:373–4.
  53. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235–44.
  54. von Minckwitz G, Muller BM, Loibl S, et al. Cytoplasmic poly(adenosine diphosphate-ribose) polymerase expression is predictive and prognostic in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol. 2011;29:2150–7.
  55. Turner NC, Ashworth A. Biomarkers of PARP inhibitor sensitivity. Breast Cancer Res Treat. 2011;127:283–6.
  56. Norquist B, Wurz KA, Pennil CC, et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011;29:3008–15.
  57. von Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012;366:299–309.
  58. Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366:310–20.
  59. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–76.
  60. Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL. Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2009;27:4966–72.
  61. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010;28:3239–47.
  62. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252–60.
  63. Smith I, Pierga JY, Biganzoli L, et al. Final overall survival results and effect of prolonged (>/=1 year) first-line bevacizumab-containing therapy for metastatic breast cancer in the ATHENA trial. Breast Cancer Res Treat. 2011;130:133–43.
  64. Choueiri TK, Mayer EL, Je Y, et al. Congestive heart failure risk in patients with breast cancer treated with bevacizumab. J Clin Oncol. 2011;29:632–8.
  65. Biganzoli L, Di Vincenzo E, Jiang Z, et al. First-line bevacizumab-containing therapy for breast cancer: results in patients aged >=70 years treated in the ATHENA study. Ann Oncol. 2012;23:111–8.
  66. Etienne-Grimaldi MC, Formento P, Degeorges A, et al. Prospective analysis of the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-based therapy in metastatic breast cancer patients. Br J Clin Pharmacol. 2011;71:921–8.
  67. Martin M, Roche H, Pinter T, et al. Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol. 2011;12:369–76.
  68. Robert NJ, Saleh MN, Paul D, et al. Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. Clin Breast Cancer. 2011;11:82–92.
  69. Nielsen DL, Andersson M, Andersen JL, Kamby C. Antiangiogenic therapy for breast cancer. Breast Cancer Res. 2010;12:209.