At the San Antonio Breast Cancer Symposium, people discussed prevention options for women at high risk for breast cancer. Tamoxifen continues to show a significant reduction in the incidence of ER-positive breast carcinomas (IBIS-1) 16 years after treatment discontinuation. If such nevertheless occurs, PI3K inhibitors may help to delay resistance to endocrine therapies in the future. However, a phase II trial (FERGI) in this area produced mixed results.
The antiestrogen tamoxifen has already been tested in four randomized trials for breast cancer prevention in healthy women and has been shown to significantly reduce disease risk in the first ten years of follow-up. Now, at the 2014 San Antonio Breast Cancer Symposium, the median 16-year blinded follow-up data from the IBIS-I trial, which examined long-term prevention with tamoxifen, were presented. 7154 premenopausal and postmenopausal women who had an increased risk of breast cancer primarily from family history had been randomized to receive either 20 mg/d tamoxifen or placebo for five years. The primary endpoint was breast cancer incidence (invasive and ductal carcinoma in situ); secondary endpoints included all-cause mortality, other cancers, and breast cancer-specific mortality.
Incidence reduction, but ambiguity regarding mortality.
After 16.2 years, 589 breast carcinomas had occurred – significantly fewer in the tamoxifen group (246) than in the control group (343). This is also reflected in the hazard ratio: under tamoxifen, the risk of breast carcinoma of all types was 29% lower than under placebo (HR=0.71[0,60–0,83], p<0.0001). Looking more closely at breast cancer subgroups, it is noteworthy that only invasive estrogen receptor (ER)-positive breast carcinomas occurred significantly less frequently under tamoxifen (HR=0.65[0,53–0,80], p<0.0001), whereas no such effect was seen in ER-negative types (HR=1.06[0,71–1,58], p=0.8). A non-significant 30% risk reduction was found for ductal carcinomas in situ. All-cause mortality increased in the tamoxifen group but did not reach significance (OR=1.10[0,88–1,38], p=0.4). No significant effects of verum were observed in breast cancer-specific mortality either. Thus, the effect of the agent on mortality remains unclear, according to the authors.
Overall, other cancers occurred slightly more frequently with tamoxifen, particularly endometrial cancer (a known side effect of tamoxifen), non-melanoma skin cancer, and lung cancer. However, the increase in other cancers was also not significant (350 vs. 315, OR=1.12[0,95–1,32], p=0.2).
Neither status (pre/postmenopausal) nor duration of observation had an impact on the results, i.e., overall risk reduction in the first ten years of follow-up was the same as that in the subsequent ten years (approximately 30%). Women who took hormone replacement therapy during treatment benefited significantly less than those without.
Increase awareness
According to the authors, the update of the IBIS-I trial shows that tamoxifen exerts a preventive effect even after treatment is stopped for a long period of time, in both premenopausal and postmenopausal women. In view of the “epidemic proportions” of breast cancer, preventive approaches that have an overall positive cost-benefit balance would be highly relevant. Of course, the side effects that appeared especially during the active treatment phase of the study should not be forgotten. Achieving that healthy women take the drug will remain difficult in any case. According to study leader Prof. Jack Cuzick, London, awareness in this area urgently needs to be improved: While it is normal to be proactive about cardiovascular risk conditions such as high blood pressure or high cholesterol, there still seems to be too little preventive awareness about breast cancer – among both physicians and patients.
The study was published in parallel with the presentation at the congress in the Lancet Oncology [1].
PI3K inhibition: circumventing resistance?
The phosphoinositide 3-kinase (PI3K) signaling pathway appears to be of central importance in ER-positive breast cancer. From preclinical and clinical data, it is thought to play a key role in resistance to endocrine therapies. This is where the concept of circumventing the resistance mechanisms by using a PI3K inhibitor concurrently with endocrine therapy comes from. The FERGI trial is the first randomized phase II trial that tested this assumption. Compared the addition of 340 mg/d pictilisib (GDC-0941) or placebo to endocrine therapy with fulvestrant (500 mg, days 1 and 15) in 168 postmenopausal women with ER-positive and HER2-negative advanced or metastatic breast cancer. Some of the patients had PIK3CA-mutated tumors, but not all. Mutations in the PIK3CA gene are associated with uncontrolled signal transduction in the PI3K pathway. Mandatory inclusion criterion was prior unsuccessful treatment with aromatase inhibitors in the adjuvant or metastatic setting. The primary endpoint was progression-free survival.
Compared with the control arm, median progression-free survival was prolonged with the addition of the PI3K inhibitor (3.8 vs. 6.2 months), which corresponded to a nonsignificant risk reduction of 23%. Mutation status mattered in that patients with wild-type benefited slightly more from the combination (3.6 vs. 5.8 months, HR, 0.64; 95% CI, 0.35-1.17) than those with mutation (5.1 vs. 6.2 months, HR, 0.92; 95% CI, 0.48-1.76). Overall, however, the differences were too weak to actually define mutation status as a relevant factor, which generated much discussion at the congress. It had been commonly expected that the PIK3CA genotype was critical for outcome.
The side effects were as expected, mainly skin rashes and gastrointestinal problems as known from phase I single agent studies. Nevertheless, they often led to dose reduction or therapy discontinuation, suggesting that optimal dosing may not have been achieved. No interaction of the two agents was evident. There were no deaths related to treatment.
Which subgroup benefited most?
An unplanned subgroup analysis showed that patients with ER- and progester- on receptor (PR)-positive breast cancer in particular benefited from the combination (3.7 vs. 7.2 months, HR, 0.46) – regardless of PIK3CA mutation status. This subgroup accounted for approximately 70% of all cases studied. Of course, the results need to be verified due to the small sample size. However, if the study is to be believed, there is a potential synergy of the two agents in any case. Further research efforts are therefore warranted. Future studies will likely turn to PI3K inhibitors other than pictilisib in this regard.
Source: San Antonio Breast Cancer Symposium, December 9-13, 2014, San Antonio.
Literature:
- Cuzick J, et al: Tamoxifen for prevention of breast cancer: extended longterm follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol 2015 Jan; 16(1): 67-75.
CONGRESS SPECIAL 2015; 6(1): 2-3
