Understanding the mechanisms of aromatase inhibitor resistance

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Abstract

Aromatase inhibitors (AIs) have a central role in the treatment of breast cancer; however, resistance is a major obstacle to optimal management. Evidence from endocrine, molecular and pathological measurements in clinical material taken before and after therapy with AIs and data from clinical trials in which AIs have been given as treatment either alone or in combination with other targeted agents suggest diverse causes for resistance. These include inherent tumour insensitivity to oestrogen, ineffective inhibition of aromatase, sources of oestrogenic hormones independent of aromatase, activation of signalling by non-endocrine pathways, enhanced cell survival and selection of hormone-insensitive cellular clones during treatment.

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Most cited references 70

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Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.

Stephen Johnston, John Pippen, Xavier Pivot … (2009)

Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.

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Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study.

Bella Kaufman, John Mackey, Michael Clemens … (2009)

TAnDEM is the first randomized phase III study to combine a hormonal agent and trastuzumab without chemotherapy as treatment for human epidermal growth factor receptor 2 (HER2)/hormone receptor-copositive metastatic breast cancer (MBC). Postmenopausal women with HER2/hormone receptor-copositive MBC were randomly assigned to anastrozole (1 mg/d orally) with or without trastuzumab (4 mg/kg intravenous infusion on day 1, then 2 mg/kg every week) until progression. The primary end point was progression-free survival (PFS) in the intent-to-treat population. Results Overall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in PFS compared with patients receiving anastrozole alone (hazard ratio = 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4 months; log-rank P = .0016). In patients with centrally confirmed hormone receptor positivity (n = 150), median PFS was 5.6 and 3.8 months in the trastuzumab plus anastrozole and anastrozole alone arms, respectively (log-rank P = .006). Overall survival in the overall and centrally confirmed hormone receptor-positive populations showed no statistically significant treatment difference; however, 70% of patients in the anastrozole alone arm crossed over to receive trastuzumab after progression on anastrozole alone. Incidence of grade 3 and 4 adverse events was 23% and 5%, respectively, in the trastuzumab plus anastrozole arm, and 15% and 1%, respectively, in the anastrozole alone arm; one patient in the combination arm experienced New York Heart Association class II congestive heart failure. Trastuzumab plus anastrozole improves outcomes for patients with HER2/hormone receptor-copositive MBC compared with anastrozole alone, although adverse events and serious adverse events were more frequent with the combination.

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Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial.

M. Baum, A U Budzar, J Cuzick … (2002)

In the adjuvant setting, tamoxifen is the established treatment for postmenopausal women with hormone-sensitive breast cancer. However, it is associated with several side-effects including endometrial cancer and thromboembolic disorders. We aimed to compare the safety and efficacy outcomes of tamoxifen with those of anastrozole alone and the combination of anastrozole plus tamoxifen for 5 years. Participants were postmenopausal patients with invasive operable breast cancer who had completed primary therapy and were eligible to receive adjuvant hormonal therapy. The primary endpoints were disease-free survival and occurrence of adverse events. Analysis for efficacy was by intention to treat. 9366 patients were recruited, of whom 3125 were randomly assigned anastrozole, 3116 tamoxifen, and 3125 combination. Median follow-up was 33.3 months. 7839 (84%) patients were known to be hormone-receptor-positive. Disease-free survival at 3 years was 89.4% on anastrozole and 87.4% on tamoxifen (hazard ratio 0.83 [95% CI 0.71-0.96], p=0.013). Results with the combination were not significantly different from those with tamoxifen alone (87.2%, 1.02 [0.89-1.18], p=0.8). The improvement in disease-free survival with anastrozole was seen in the subgroup of hormone-receptor-positive patients, but not the receptor-negative patients. Incidence of contralateral breast cancer was significantly lower with anastrozole than with tamoxifen (odds ratio 0.42 [0.22-0.79], p=0.007). Anastrozole was significantly better tolerated than tamoxifen with respect to endometrial cancer (p=0.02), vaginal bleeding and discharge (p<0.0001 for both), cerebrovascular events (p=0.0006), venous thromboembolic events (p=0.0006), and hot flushes (p<0.0001). Tamoxifen was significantly better tolerated than anastrozole with respect to musculoskeletal disorders and fractures (p<0.0001 for both). Anastrozole is an effective and well tolerated endocrine option for the treatment of postmenopausal patients with hormone-sensitive early breast cancer. Longer follow-up is required before a final benefit:risk assessment can be made.

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Author and article information

Contributors

William R Miller

Alexey A Larionov

Journal

Journal ID (nlm-ta): Breast Cancer Res

Journal ID (iso-abbrev): Breast Cancer Res

Title: Breast Cancer Research : BCR

Publisher: BioMed Central

ISSN (Print): 1465-5411

ISSN (Electronic): 1465-542X

Publication date (Print): 2012

Publication date (Electronic): 19 January 2012

Publication date PMC-release: 19 July 2012

Volume: 14

Issue: 1

Page: 201

Affiliations

[1 ]University of Edinburgh, Stoneycroft Road, South Queensferry, West Lothian, EH30 9HX, UK

[2 ]Edinburgh Breakthrough Breast Research Unit, Western General Hospital, Edinburgh EH4 2XU, UK

Article

Publisher ID: bcr2931

DOI: 10.1186/bcr2931

PMC ID: 3496110

PubMed ID: 22277572

SO-VID: 380a8cfe-58ba-42d6-9b87-807101c4d655

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