Breast cancer update

This content is part of a paid partnership with Breast Cancer Research Centre-WA.

Updates in endocrine therapy for metastatic hormone receptor positive advanced breast cancer management and mechanisms of overcoming endocrine resistance.

The oestrogen receptor has been a molecular target for treatment in this breast cancer (BC) subtype for over four decades, since the development of the selective oestrogen receptor modulator (SERM), Tamoxifen. This was followed by aromatase inhibitors (AI) and selective estrogen receptor degrader (SERD), fulvestrant. As hormone receptor (HR) positive advanced breast cancer (ABC) utilises estrogen to support and promote its growth, it is a powerful target of therapy and the mainstay of first and subsequent line treatment. 

Treatment resistance, however, remains a challenge for patients with the majority of patients having metastatic disease that progresses despite an initial response. 

Endocrine Resistance Definition

Patients who have had previous early-stage treatment may have primary resistance (relapse within 2 years of commencing adjuvant therapy) or secondary resistance (relapse after two years of commencement of endocrine therapy). The patient is considered to have endocrine sensitive disease if there is a minimum of twelve months of remaining disease-free after adjuvant therapy completion.

Mechanisms of Endocrine Resistance

One of the mechanisms of resistance stems from mutations in the breast cancer cell genome. The most well documented targetable acquired mutations include the oestrogen receptor mutation (ESR1), at the oestrogen binding domain, and altered regulation of the cell cycle including cyclin D1 and CDK4/6 overexpression. PIK3CA gene mutation is another targetable mechanism of resistance. These mutations can be detected in up to 40% of treated ER positive ABC. Other mechanisms of resistance include loss of ER expression and other cellular growth signal pathway molecules such as upregulation of mTOR. 

First Line Therapy

In cases of de novo or relapsed estrogen receptor positive metastatic BC, the current evidence is to commence treatment with an AI and a CDK4/6 inhibitor (ribociclib, palbociclib or abemaciclib) based on multiple phase III trials confirming benefit. There have been no head to head studies comparing the different CDK 4/6 inhibitors and all are PBS-subsidised. The MONALEESA-2 trial updated in 2022, with a median follow up of 6.6 years has seen an improvement in overall survival from 51.4 months to 63.9 months with the addition of ribociclib to letrozole v letrozole and placebo. There is no overall survival data yet for palbociclib or abemaciclib, but both treatments have progression free survival benefits and are used in clinical practice. 

Therapy In Endocrine Resistant Patients

CDK4/6 Inhibitors

CDK4/6 inhibitors have shown to be effective, even in heavily pre-treated patients. In patients with endocrine resistant disease, the first line therapy of choice is a CDK4/6 inhibitor combined with a SERD. The MONARCH2 trial with abemaciclib, which exclusively enrolled endocrine resistant patients for first line metastatic therapy (approximately 25% had primary resistance) has an overall survival benefit when combined with fulvestrant of 9.4 months compared with fulvestrant alone. Ribociclib and palbociclib have also shown efficacy in endocrine resistant patients when combined with fulvestrant. All three agents have been PBS subsidised for use with fulvestrant in endocrine resistant disease.

SERDs

Selective estrogen receptor degraders (SERDs) have proven efficacy in ESR1 mutation, as it degrades the receptor, thereby blocking nuclear signalling. Two examples include fulvestrant or newer oral agent, elacestrant. Elacestrant was recently reported in the EMERALD trial as an effective single agent in patients pre-treated with ≤ 2 lines of endocrine therapy (including CDK4/6 inhibitors) with a 12 month PFS rate of 22.3% in the treatment arm v 9.4% in the standard of care arm. This benefit was seen regardless of ESR1 mutation status, but a stronger effect was seen in this subgroup. It is not currently available as PBS-subsidised treatment. 

PIK3CA/ACT/mTOR Pathway

Growth signalling pathways in breast cancer cells are another molecular target. PIK3CA can be targeted with alpelisib. In the SOLAR-1 trial alpelisib combined with fulvestrant had a significant PFS of 11 v 5.7 months compared with fulvestrant alone in patients with a PICK3CA mutation. Approximately 70% of patients had endocrine resistant disease and patients were allowed to have had previous CDK4/6 inhibitor treatment. Alpelisib is not yet available on the PBS for treatment.

The mTOR inhibitor, everolimus, in combination with an AI has PFS benefit in endocrine resistant ABC and is available on the PBS.

Conclusion

Endocrine therapy alone on in combination with newer targeted agents offer a relatively low toxicity (as compared to chemotherapy) and high activity treatment option for ER positive ABC and is the backbone of first line treatment. In order to delay or overcome ET treatment resistance molecular targeted treatments have been added to sequential endocrine therapies and are improving PFS and OS in ABC.

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