In 2020, breast cancer replaced lung cancer as the most common cancer in the world.[1] As the world's most populous country, China contributes more than 11% of the global
breast cancer cases in 2018.[2]
[3] The human epidermal growth factor receptor-2-negative (HER2−) luminal subtype (hormone receptor-positive [HR+] and HER2−) represents approximately 70% of all breast cancer cases.[4]
[5] Endocrine-based therapy is the recommended initial treatment for HR+ and HER2− advanced breast cancer patients.[6]
[7] This treatment strategy can maintain the quality of life (QoL) for advanced breast
cancer patients as long as possible before they switch to chemotherapy. Indeed, endocrine-based
therapy combined with rapamycin inhibitors, CDK4/6 inhibitors, or PI3K inhibitors
improves progression-free survival (PFS) of advanced breast cancer patients, and thereby
delaying chemotherapy.[4]
[8] Therefore, adding the three types of targeted therapy drugs mentioned above to endocrine-based
therapy before initiating chemotherapy is now considered the standard of care. Several
previous studies have demonstrated that CDK4/6 inhibitors could maintain QoL in patients
with advanced breast cancer.[9] However, QoL data in patients treated with PI3K inhibitors have not been reported.
It is worth noting that approximately 40% of HR+ and HER2− breast cancer patients carry phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic
subunit α (PIK3CA) gene mutations.[4]
[10] In addition, these mutations are associated with a poor prognosis for advanced breast
cancer patients.[10]
[11]
SOLAR-1 is a randomized, phase III trial which compared alpelisib (a PI3K inhibitor)
plus fulvestrant with placebo plus fulvestrant in patients with recurrence/progression
of HR+ and HER2− advanced breast cancer who had received endocrine therapy (aromatase inhibitor-based
treatment) previously.[4]
[12] It showed that alpelisib plus fulvestrant increased median PFS versus placebo plus
fulvestrant (11.0 vs. 5.7 months). Unfortunately, as PI3Kα is also involved in normal
human physiological processes, PI3Kα inhibitors can cause treatment-related adverse
events, such as diarrhea, hyperglycemia, and rash.[4]
Since the treatment for advanced breast cancer is palliative treatment, health-related
QoL is the key factor in evaluating the risk-benefit status of treatment.[13] Patients with advanced breast cancer often experience pain and impaired QoL related
to disease progression and treatment side effects. Pain and impaired QoL are important
factors in treatment decisions for such patients.[14] Therefore, there is an urgent need to understand the effects of alpelisib on pain
and QoL. In a study recently published in Journal of Clinical Oncology, titled “Patient-reported outcomes in patients with PIK3CA-mutated hormone receptor-positive,
human epidermal growth factor receptor 2-negative advanced breast cancer from SOLAR-1,”
Ciruelos and colleague[15] assessed the health-related QoL using standardized patient-reported outcomes measure
in advanced breast cancer patients with PIK3CA mutations, HR+, and HER2− who were enrolled in SOLAR-1 trial.
In this study, a total of 341 patients with PIK3CA mutations were enrolled and randomly assigned (1:1) to receive alpelisib plus fulvestrant
or placebo plus fulvestrant. European Organization for Research and Treatment of Cancer
QoL of Cancer Patients and Brief Pain Inventory-Short Form questionnaires were used
to evaluate the patient-reported outcomes. Repeated measurement models and Cox models
were used to analyze the alterations from baseline and time to 10% deterioration,
respectively. Global Health Status/QoL and functional status were maintained from
baseline in the alpelisib and placebo arms (overall change from baseline [95% confidence
interval]: −3.50 [−8.02 to 1.02] for the alpelisib arm and 0.27 [−4.48 to 5.02] for
the placebo arm). The overall treatment effect in Global Health Status/QoL was not
statistically different between the alpelisib and placebo arms (−3.77; 95% confidence
interval = −8.35 to 0.80; p = 0.101). Time to 10% deterioration for Global Health Status/QoL was not significantly
different between arms (hazard ratio = 1.03; 95% confidence interval = 0.72–1.48).
Compared with the patients treated with placebo, patients treated with alpelisib experienced
deterioration in social functioning, diarrhea, loss of appetite, nausea or vomiting,
and fatigue. Additionally, numerical improvement in worst pain was observed in the
patients treated with alpelisib when compared with their placebo counterparts (42
vs. 32%; p = 0.090).
The SOLAR-1 study has proven that adding alpelisib to fulvestrant treatment can improve
the median PFS of patients with PIK3CA-mutant advanced breast cancer.[4] Moreover, the present study demonstrated that fulvestrant plus alpelisib did not
have a significant impact on QoL except with deterioration in social functioning as
compared with fulvestrant alone. In addition, the worsening of pain and numeric improvement
in worst pain in patients receiving the combination therapy of alpelisib and fulvestrant
were delayed. However, patients who received alpelisib plus fulvestrant showed a slight
decrease in social functioning subscale and symptom subscale scores (such as diarrhea
and loss of appetite). The decline in these scores was basically consistent with the
profiles of adverse event observed with the treatment of alpelisib plus fulvestrant.[4] This can be explained as diarrhea and loss of appetite may lead to a decline in
social functioning. Since this study observed that the overall QoL of patients receiving
alpelisib plus fulvestrant was not statistically different from that of patients received
placebo plus fulvestrant, we speculated that the negative impact of adverse event-related
symptoms on QoL was partly due to the delay in disease progression. Some patients
enrolled in the SOLAR-1 trail discontinued the treatment of alpelisib or placebo because
of adverse events, but continued fulvestrant treatment,[4] which might have also contributed to the delay in worsening of QoL. It is noteworthy
that median PFS was shorter than time to 10% deterioration in each subscale. This
finding indicates that the negative impact on functioning scores is mainly due to
disease progression rather than study treatment.
This study has several limitations. Like all oncology studies that collect QoL questionnaires
longitudinally, the main limitation of this study is missing data. In this regard,
the authors followed United States National Research Council principles for analyzing
incomplete data to assess the reasons for missing data and conduct a sensitivity analysis.
They found that disease progression was the main reason for missing QoL data, followed
by the discontinuation of study treatment due to treatment-related toxicity, but administrative
reasons for missing data were considered to be non-informative. Another limitation
relates to change over time in QoL. The 95% confidence interval for the change from
baseline in the alpelisib arm ranged from −8.02 to 1.02, while that in the placebo
arm ranged from −8.35 to 0.80. The difference between the two is −3.77. Although this
study did not observe a statistical difference between alpelisib arm and placebo arm,
the upper limit of the 95% confidence interval was extremely close to 0. However,
the mean difference and the lower limit are both within 0 and 10 points, indicating
that the magnitude of the difference was small. Both the significance and magnitude
should be considered when evaluating treatment effects. Although this study still
has the limitations mentioned above, this study still proved that the overall QoL
of advanced breast cancer patients with HR+HER2− and PIK3CA mutations was maintained with alpelisib plus fulvestrant treatment.
