Q1. How is risk stratification performed in clinical practice, and how do you decide if a patient with hormone-receptor positive breast cancer is suited for endocrine monotherapy, targeted combination therapy or chemotherapy?
Of the current classifications of breast cancer, hormone-receptor positive (oestrogen and/or progesterone) is the most common and accounts for 60–75% of all cancers.1 Current treatment guidelines recommend endocrine therapy as the preferred option for hormone-receptor positive breast cancer, unless there is a visceral crisis or concern/proof of endocrine resistance.2 Endocrine therapies include aromatase inhibitors (e.g. anastrozole, letrozole, exemestane), oestrogen receptor modulators (e.g. tamoxifen) and selective oestrogen-receptor degraders (e.g. fulvestrant).3
However, de novo resistance to endocrine therapy occurs in approximately 40% of patients,3 and even in tumours where initial endocrine therapy is effective, acquired resistance can occur due to selective pressure and tumour evolution.4 To address this, new therapies are being developed to restore endocrine sensitivity in resistant tumours by targeting signal transduction pathways thought to be involved in the ligand-independent activation of hormone receptors. These include cyclin-dependent kinase (CDK) 4/6 inhibitors (e.g. palbociclib, ribociclib, abemaciclib), phosphoinositide 3 kinase (PI3K) inhibitors (e.g. buparlisib) and mammalian target of rapamycin inhibitors (e.g. temsirolimus, everolimus).3 As such, where there used to be only the option of single-agent endocrine therapy or chemotherapy for hormone-receptor positive breast cancer, there are now multiple potential strategies available to the physician.
The decision whether to use single-agent endocrine therapy, combination endocrine therapy or chemotherapy depends on a number of factors, most of which can be grouped into two main categories: (i) disease activity, and (ii) potential endocrine sensitivity. Disease activity includes the site of the tumour, the speed of tumour growth (e.g. proliferation rate as measured by Ki-675), the presence of bone metastases or visceral metastases, the degree of tumour burden (the number and site of tumours, e.g. in the liver or the lungs), and the time of relapses, symptoms and/or metastases relative to previous therapies. Endocrine sensitivity is not just limited to whether the tumour is likely to be endocrine sensitive (to both oestrogen and/or progesterone receptors), but also includes age, menopausal status and the likelihood of primary or acquired hormone resistance. Additional considerations include previous therapies and toxicities, co-morbidities (including organ dysfunctions), psychological factors and patient preferences.2
However, all of these factors are considered relatively ‘soft’ markers for treatment selection. As there are no established driver mutations for breast cancer that might recommend specific single-agent, combination or chemotherapies, it is only by combining multiple factors to build up a patient profile that a physician can judge whether a patient has: (i) low disease activity and a relatively low risk of failure with a single-agent endocrine therapy, or (ii) a medium-to-high risk of failure with single-agent endocrine therapy and who should therefore receive combination endocrine therapy or chemotherapy.3
Q2. How can this decision-making process be made less subjective in the future?
Unfortunately, there is a great deal of heterogeneity in hormone-receptor positive breast cancer, and so it remains a challenge to make this decision-making process objective. There is no clear ‘cutoff’ or timepoint that defines a switch from single-agent to combination endocrine therapy, and the decision to do so is based largely on the clinical experience of the physician. However, there are several ongoing studies that might necessitate a re-examination of treatment selection and sequencing guidance: FALCON (NCT01602380), PALOMA-2 (NCT01740427) and MONALEESA-2 (NCT01958021).3 Should these studies show benefits on overall survival and progression-free survival with fulvestrant + CDK 4/6 inhibitor combination therapy compared with single-agent therapies, the earlier use of combination therapies in hormone-receptor positive breast cancer may be recommended.
Recent advances in the molecular and genetic understanding of breast cancer tumours may also provide information to help guide treatment selection. In particular, mutations in the ESR1 gene have been shown to confer resistance to endocrine therapy, and are present in 20% of metastatic oestrogen-positive receptor cancers.6 Clinical benefit has been reported with fulvestrant + CDK 4/6 inhibitor combination therapy in patients with non-visceral disease and the ESR1 mutations status, with objective response rates of over 40%.3 Looking to the future, it is hoped that we will be able screen for multiple genes and proteins to identify the best treatment for a patient. However, it is likely that there will always be an element of subjectivity in the treatment selection process.
Support: This Insight article was supported by AstraZeneca.
Acknowledgements: Medical writing assistance was provided by Stuart Wakelin at Touch Medical Media.
1. Cancer.Net. Breast Cancer: Introduction. Available at: www.cancer.net/cancertypes/breast-cancer/introduction (accessed November 2017).
2. Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO international consensus guidelines for Advanced Breast Cancer (ABC 3). Breast. 2017;31:244–59.
3. Schmid P. Endocrine Therapeutic Strategies for Patients with Hormone Receptor-positive Advanced Breast Cancer. European Oncology & Haematology. 2017;13(2):127–33.
4. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233–47.
5. Inwald EC, Klinkhammer-Schalke M, Hofstadter F, et al. Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry. Breast Cancer Res Treat. 2013;139:539–52.
6. Jeselsohn R, Buchwalter G, De Angelis C, et al. ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12:573–83.
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