Oestrogen receptor (ER)-positive, HER2-negative breast cancer accounts for about 70% of all diagnosed breast cancer cases, and endocrine therapy is its cornerstone treatment, both in the early and advanced disease settings. However, not all ER-positive breast cancer responds optimally to endocrine therapy. Upregulation of the PI3K–AKT–mTOR pathway is one of the mechanisms that can lead to primary or secondary endocrine resistance, or both.1 Genes in the PI3K–AKT–mTOR pathway are frequently mutated or amplified in breast cancer, especially in the ER-positive subtype. PIK3CA (encoding p110α, the catalytic subunit of PI3Kα) is mutated in about 35% of all breast cancers, and is more frequent in ER-positive tumours.2
Targeting the PI3K–AKT–mTOR pathway in ER-positive breast cancer has proved beneficial both in the neoadjuvant and in the advanced settings.3, 4 In the BOLERO-2 trial, the addition of everolimus to exemestane improved progression-free survival in patients with hormone receptor-positive disease, but efficacy was not increased in those with PIK3CA-mutant tumours,4, 5 suggesting that direct inhibitors of PI3K could be a preferred option in these patients. In line with this hypothesis, a phase 3 trial testing the pan-PI3K inhibitor buparlisib in combination with fulvestrant showed increased activity in those patients with a PIK3CA mutation detected in circulating tumour DNA (ctDNA).6 Although these results were encouraging, pan-PI3K inhibitors were frequently associated with hyperglycaemia, dermatological and gastrointestinal adverse events, fatigue, and pneumonitis.6, 7, 8 Mood disorders were reported in nearly a third of patients and a higher proportion of patients receiving buparlisib showed suicidal ideations and attempts,6, 7 which discouraged its approval. Conversely, PI3K isoform-specific agents, such as taselisib and alpelisib, have shown a better safety profile and their most common adverse events (eg, hyperglycaemia, rash, diarrhoea, and mucositis) are amenable to medical management if early interventions are indicated.9, 10, 11
Taselisib (GDC-0032) inhibits the PI3K-β isoform 30 times less potently than the α-isoform and shows enhanced activity against PIK3CA-mutant versus wild-type forms.12 Taselisib as single agent is well tolerated and has shown antitumour activity across multiple tumour types.13 The combination of taselisib with letrozole or fulvestrant induced several partial responses in heavily pretreated patients with metastatic, ER-positive breast cancer, especially in tumours harbouring a PIK3CA mutation,14 suggesting that the addition of taselisib to hormone therapy might be a potential therapeutic choice for patients with PIK3CA-mutant breast cancer.15
The neoadjuvant setting provides a unique opportunity to identify predictive biomarkers of response to novel therapeutic agents. Pretreatment biopsies are easily accessible, on-treatment biopsies can monitor treatment response at a biological level and, if a pathological complete response is not achieved, the surgical specimen can be examined for mechanisms of resistance to therapy. The biological information obtained from all specimens can be correlated with clinical data, such as objective response and pathological complete response, a surrogate endpoint that strongly associates with disease-free and overall survival in patients with some subtypes of breast cancer.16
Research in context
Evidence before this study
We searched PubMed for publications between Jan 1, 2001, and Sept 30, 2017, with the search terms “PIK3CA mutation”, “PI3K alpha-specific inhibitors”, “neoadjuvant endocrine”, and “ER+/HER2-negative early breast cancer”. We also searched PubMed for publications in the same period describing assessment of taselisib using the terms “taselisib” or “GDC-0032”. No previous randomised trials had investigated the targeting of PI3K specifically in oestrogen receptor (ER)-positive, HER2-negative early breast cancer. Analyses of preclinical studies and single-group phase 1 or phase 2 studies in ER-positive, HER2-negative, metastatic breast cancer have suggested a more pronounced effect of isoform selective inhibitors in cell lines, preclinical models, and patients harbouring a PIK3CA mutation.
Added value of this study
Our results suggest that taselisib increases the efficacy of letrozole in postmenopausal women with hormone receptor-positive, HER2-negative, operable breast cancer, because this combination results in a higher proportion of patients who achieved an objective response, especially in patients harbouring PIK3CA-mutant tumours. The safety profile of taselisib was consistent with previous reports and related toxicities were tolerable and manageable with early medical interventions.
Implications of all the available evidence
Targeting the mTOR–PI3K pathway combined with endocrine therapy is an active treatment option in this setting for hormone receptor-positive, HER2-negative, advanced breast cancer. The efficacy of taselisib in the neoadjuvant setting is consistent with the clinical benefit reported in the SANDPIPER trial in which taselisib plus fulvestrant resulted in longer progression-free survival than fulvestrant alone in patients with PIK3CA-mutant metastatic cancer. Our results and available data from phase 1–3 trials of taselisib in advanced disease, although limited by differences in sample sizes, tissues analysed, and populations included, suggest that PIK3CA mutations might help in selecting patients who benefit from targeting PI3K. Further studies are required to identify response and resistant biomarkers for these agents.
However, MRI has been shown to be more accurate than clinical palpation, ultrasound, and mammogram for measuring residual tumour size after neoadjuvant therapy in several prospective trials.17 In the I-SPY1 trial,18 breast functional tumour volume by MRI (tumour volume enhancement >70% after neoadjuvant chemotherapy) was a strong predictor of relapse-free survival in patients with ER-positive, HER2-negative breast cancer. In another study including ER-positive, HER2-negative tumours, absolute tumour size by MRI after neoadjuvant chemotherapy and radiological complete response but not pathological complete response was associated with relapse-free survival.19
In the LORELEI trial, we aimed to assess the efficacy and safety of neoadjuvant taselisib and letrozole in the treatment of patients with ER-positive, HER2-negative, early breast cancer and investigated the presence of a PIK3CA mutation as a biomarker for response.