Liquid Biopsies to Predict Therapeutic Response – The SOLAR-1 Study

Breast cancer is a heterogeneous disease and its prognosis can vary widely according to its biological subtype. Expression of hormone receptors (HRs; comprising oestrogen receptors and progesterone receptors) and human epidermal growth factor receptor-2 (HER2) are routinely used to guide treatment decisions.¹ However, this approach is limited in terms of predicting the risk for recurrence and treatment resistance. The most common subtype of breast cancer is HR-positive breast cancer, which accounts for approximately 60–70% of all cases.¹ Around 40% of these have mutations of the p110α subunit of the phosphatidylinositol 3-kinase (PI3K) gene (PIK3CA), which activate the PI3K pathway, resulting in tumour progression and resistance to endocrine therapy.² Alpelisib is a selective oral inhibitor of the alpha subunit of PI3K inhibitor that has shown promising efficacy and safety in a phase I study.³
The SOLAR-1 study investigated the efficacy and safety of alpelisib plus fulvestrant in 572 patients (men and postmenopausal women) with HR positive, HER2-negative advanced breast cancer, who had received prior treatment with an aromatase inhibitor.⁴ These were randomly assigned to oral alpelisib (300 mg/day) or placebo plus injected fulvestrant (500 mg every 28 days and on days 1 and 15 of treatment cycle 1). Examination of tumour tissue revealed PIK3CA mutations in 341 patients. The primary endpoint was locally assessed progression-free survival (PFS) in patients with PIK3CA mutations. Results showed that, at a median follow-up of 20 months, the progression-free survival (PFS) was almost twice as long in patients with PIK3CA mutations randomly assigned to receive alpelisib compared to the placebo group. (11.0 months versus 5.7 months; hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.50–1.25; p=0.00065). The most frequent side effects with alpelisib compared with placebo were hyperglycaemia (65% versus 9%), nausea (54% versus 11%), decreased appetite (6% versus 20%), and rash (40% versus 6%). Hypoglycaemia was managed without dose adjustment in 41% of patients, with dose adjustment in 49%, and early use of insulin sensitizers in 76%.⁴ Insulin resistance resulting in hyperglycaemia is a known complication of PI3K-alpha inhibition.⁵ Regular monitoring of blood glucose levels, followed by dietary modification and/or metformin in cases of hyperglycaemia, is essential to the management of these patients.

The primary endpoint of the SOLAR-1 trial was determined based on PIK3CA mutations in any available tumour tissue, such as archival or fresh tissue. However, data presented at the 2018 San Antonio Breast Cancer Symposium, which was held on 4–8 December 2018, showed that a liquid biopsy, based on the assessment of PIK3CA mutations in circulating tumour DNA (ctDNA) in the plasma, was a better indicator of PFS than the analysis of tissue biopsy. Patients with PIK3CA mutations as determined by tissue samples had a 35% reduction in risk for disease progression. However, the risk reduction was 45% for patients with PIK3CA mutations, a much closer correlation with actual clinical outcomes.⁶

This analysis also assessed PFS by line of metastatic treatment, as well as prior exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Patients with metastatic breast cancer who received alpelisib as second-line therapy had a 39% reduction in risk for disease progression compared to those who received placebo. The risk reduction was 33% for those who did not receive prior treatment with CDK4/6 inhibitors.⁶

The advantages of a liquid biopsy are clear. Apart from the invasiveness of tissue biopsy, heterogeneity within the tumour may compromise the accuracy of a tissue biopsy since only a limited amount of tissue may be sampled and may not be representative of all the changes occurring within the tumour.⁷ Previous studies have established that ctDNA is a specific and highly sensitive biomarker in identifying mechanisms of resistance to ongoing therapies in patients with breast cancer as well as identifying new targets for further treatment.^8,9.

Lead author Dejan Juric, MD (Director of the Termeer Centre for Targeted Therapies at the Massachusetts General Hospital Cancer Centre, Boston, Massachusetts, US) said: “PIK3CA mutation testing can be performed on archival or fresh tumour tissue, but this material may not be available in all patients, particularly in those with difficult-to-reach visceral lesions or bone metastases. Compared to tissue DNA, circulating tumour DNA is a very easily accessible source of material for mutation profiling. The finding that assessing mutational status via liquid biopsy resulted in even larger clinical benefit compared to tissue biopsy, with improvement of median PFS from 3.7 months to 10.9 months, further highlights the clinical utility of this biospecimen.”⁶

At present, we have a limited number of drugs available to treat tumours associated with other specific molecular alterations, but this is an active area of clinical research. One type of actionable genetic alteration that can be detected by this approach is mutations in the ESR1 gene, which encodes the oestrogen receptor and is increasingly recognised as an important mechanism of resistance to endocrine therapy.¹⁰

A potential limitation of this approach is the fact that currently available assays are less sensitive than tissue-based tests. In addition, there is the potential for contamination by DNA arising from white blood cells.¹¹ Before liquid biopsies become routinely used in the clinic, further studies are needed to fully establish the relationship between abnormalities in ctDNA detected in the blood with findings in tissue biopsies and with clinical outcomes.

In summary, the SOLAR-1 study has broken new ground as the first to show that treatment based on the genetic profile of a patient’s tumour can improve clinical outcomes and potentially heralds a new era of clinical genomic testing for breast cancer. Assessing PIK3CA mutations by minimally invasive liquid biopsies may become the standard of care for patients with HR-positive breast cancer. Other potential clinical applications of liquid biopsy in breast cancer include use as a screening tool, and for monitoring treatment response. Although these applications are some distance from becoming routine clinical practice, recent data and ongoing research is leading the way to a new era in the management of breast cancer.