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Published on 20 September 2010

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Combination of treatments for breast cancer

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The combination of lapatinib and letrozole provides an effective and tolerable alternative for women with breast cancer who cannot undergo treatment with chemotherapy

Dr Siobhan O’Neill
MBBS FRACP

Professor Stephen Johnston
FRCP PhD
Department of Medicine (Breast Unit)
Royal Marsden NHS Foundation Trust
London, UK

Breast cancer is the most common cancer among women worldwide. Within Europe 421,000 new cases are diagnosed each year with a lifetime risk of 1 in 9.[1] It is a heterogeneous disease, with current therapeutic strategies being based to a large extent on tumour expression of hormone receptors (HR) and human epidermal growth factor receptor 2 (HER2).
Oestrogen receptors (ER) are over-expressed in approximately 70% of breast cancers. Standard treatment of post-menopausal ER-positive breast cancer consists of using either selective oestrogen receptor modulators (SERMS), which behave as ER antagonists in breast tissue, or aromatase inhibitors, which cause oestogen deprivation by preventing the conversion of androgens to oestrogens within the adrenal glands and peripheral adipose tissue. Invariably however, resistance to these agents develops, with disease progression. Cross-talk between cell signalling pathways of the epidermal growth factor family of receptors – ErbB1 (epidermal growth factor receptor [EGFR]) and ErbB2 (human epidermal growth factor receptor 2 [HER2]) – and the oestrogen receptor are thought to contribute to the development of resistance.[2,3]
Over-expression of the HER2 protein occurs in 20% of breast cancers and is a known independent poor prognostic factor. The cornerstone of treatment for these tumours is anti-HER2 targeted agents, either in the form of trastuzumab, a monoclonal antibody, or lapatinib, a small molecule dual tyrosine kinase inhibitor (TKI). Due to the often more aggressive nature of HER2-positive cancer and the need for a rapid clinical response to therapy, the standard treatment has been to combine anti-HER2 therapy with chemotherapy. There are, however, several clinical settings in which a less aggressive approach, with potentially less toxicity, may be more appropriate, such as in frail patients with multiple comorbidities, or when there is a low burden of disease with slow progression.
While approximately 50% of HER2-positive cancers co-express hormone receptors, minimal benefit seems to be gained from single agent hormonal therapy.[3,4] Certainly, preclinical and clinical data suggest that HER2 over-expression confers intrinsic resistance to endocrine treatment.[5,6] Two large randomised first-line clinical trials have demonstrated that the combination of endocrine manipulation with anti-HER2 therapies in HR-positive HER2-positive breast cancer may overcome this resistance, and represents a well tolerated and more efficacious alternative to endocrine therapy alone.[2,4] These trials did not, however, provide a direct comparison with combined anti-HER2 agents and chemotherapy, which is discussed further below.
The Trastuzumab in Dual HER2 ER-Positive Metastatic Breast Cancer (TAnDEM) trial demonstrated that the addition of trastuzumab to the aromatase inhibitor anastrazole doubled the median progression-free survival (PFS) compared to anastrazole alone (4.8 vs 2.4 months).[4]
Similarly, the EGF30008 study compared the combination of letrozole plus lapatinib with letrozole plus placebo as first-line treatment in 1,286 post-menopausal patients with HR-positive MBC. Included in this was a sub-population of patients with known HER2-positive tumours (n=219). Within the HER2-positive subgroup, the response rate (RR) was half of that observed in the whole group (15% vs 32%), providing definitive evidence that HER2-positive tumours are less responsive to endocrine therapy. The addition of lapatinib increased the RR to 28%, and the median PFS from 3.0 months to 8.2 months. The clinical benefit rate was also significantly greater in the lapatinib plus letrozole arm. Furthermore, the benefit was seen across all known prognostic factor subgroups, including patients resistant to prior endocrine therapy and those with liver metastases or more than three sites of metastatic disease.  In HER2-negative tumours, the combination of lapatinib and letrozole did not improve PFS compared to letrozole alone, although a nonsignificant trend towards prolonged PFS from 3.1 to 8.3 months was seen in patients who had relapsed within six months of prior tamoxifen discontinuation.[2,3]

Lapatinib
Lapatinib is a potent, orally active, dual tyrosine kinase inhibitor (TKI) against the EGFR and HER-2. It is active in both trastuzumab-naïve and pre-treated HER2-positive MBC, and can be co-administered with letrozole without pharmacokinetic interaction.[2]
Lapatinib is licensed in Europe for use in combination with capecitabine in advanced or metastatic HER2-positive breast cancer, in patients who have progressive disease following prior therapy with anthracyclines, taxanes and trastuzumab in the metastatic setting. This is based on the findings from the EGF100151 trial which demonstrated increased time to progression in the lapatinib plus capecitabine arm compared to capecitabine alone (6.2 months vs 4.3 months).[7]
In February 2010 the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), based on the EGF30008 study, issued a positive opinion for the authorisation of the use of lapatinib in combination with an aromatase inhibitor in post-menopausal women with HR positive HER2-over-expressing metastatic breast cancer for whom chemotherapy is currently not intended.[8]

Dosing
The EGF30008 regimen consisted of lapatinib 1,500 mg orally daily given with letrozole 2.5 mg orally daily.

Safety
It should be noted that all patients enrolled in the EGF30008 study required a good performance status (Eastern Cooperative Oncology Group performance status of 0 or 1), normal organ function and a left ventricular ejection fraction (LVEF) within the institutional normal range for entry into the study. Patients with extensive symptomatic visceral disease were excluded.
The combination of lapatinib and letrozole was well tolerated with a high rate of compliance. Toxicities were manageable, with the most common being grade 1 and 2 diarrhoea (68%) and rash (46%). The incidence of nausea, fatigue and arthralgias was similar to that seen in letrozole monotherapy. While 10% of patients experienced grade 3 or 4 diarrhoea, the majority of these were able to be managed by dose reduction (19%), dose interruption (36%) or supportive intervention without dose adjustment (31%), with only 15% requiring discontinuation of lapatinib. Treatment-related symptomatic LVEF decline was uncommon (occurring in 0.8% of patients). Elevation of liver transaminases was infrequent, occurring in eight patients, two of whom required drug discontinuation with normalisation of tests thereafter. Liver function abnormalities resolved in the remaining six patients without drug discontinuation.

Discussion and conclusion
The EGF30008 study demonstrates that the addition of the tyrosine kinase inhibitor lapatinib to the aromatase inhibitor letrozole leads to a significant improvement in RR and PFS in patients with HR-positive HER2-positive tumours compared to letrozole alone. The combination is safe and causes few adverse effects.
It is clear from available evidence that anti-HER2 therapy should provide the backbone of treatment for HER2-positive advanced breast cancer, with increased benefit when added to either chemotherapy or endocrine therapy. It is less clear when hormonal therapy can be used in preference to chemotherapy in this population. Direct comparisons of efficacy between studies of first-line chemotherapy with or without trastuzumab to endocrine and anti-HER2 targeted combinations is not possible as the population of women with HER2-positive MBC treated within the studies differs significantly in several ways. Within the TAnDEM and EGF30008 studies all women with HER2-positive disease had HR-positive disease compared to only 40–60% in the chemotherapy studies. In addition, patients within the endocrine trials were older (median age 60 vs 53–55yrs) and had a lower incidence of visceral metastases.[2,9]
In women with HR-positive, HER2-positive metastatic breast cancer with rapidly progressive disease, or where there is significant visceral involvement when a rapid response to treatment is required, chemotherapy combined with anti-HER2 therapy should continue to be the appropriate choice. With careful clinical application, such as in women with a lower burden of disease, or who are deemed inappropriate for chemotherapy due to frailness or comorbidities, the combination of lapatinib and letrozole provides an effective and tolerable alternative. Indeed, a significant proportion of these women may derive prolonged benefit in addition to enjoying the convenience of oral therapy.

References
1. Available online at: http://info.cancerresearchuk.org/cancerstats/types/breast/incidence/
2. Johnston S et al. J Clin Oncol 2009;27:5538–46.
3. Schwarzberg LS et al. The Oncologist 2010;15:122–29.
4. Kaufman B et al. J Clin Oncol 2009;27:5529–37.
5. Pietras R et al. Oncogene 1995;10:2435–46.
6. Shin I et al. Clin Cancer Res 2006;12:1008s–12s.
7. Geyer CE et al. NEJM 2006;355:2733–43.
8. Available online at: www.gsk.com/media/pressreleases/2010
9. Cortes J and Baselga J. J Clin Oncol 2009;27:5492–93.

Acknowledgement
Dr Siobhan O’Neill would like to thank the Cridlan Fund for supporting her in undertaking this review.



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