1. Adjuvant endocrine therapy for premenopausal receptor-positive early breast cancer
1.1 A randomized phase III study comparing exemestane/tamoxifen combined with ovarian function inhibition for premenopausal HR+ early breast cancer.
It is currently believed that the most definitive agent for adjuvant endocrine therapy after surgery for premenopausal receptor-positive early breast cancer is tamoxifen, and ovarian depression is recommended for patients at high risk of recurrence who do not have amenorrhea as a result of chemotherapy, or for patients at intermediate risk of recurrence who do not wish to receive adjuvant chemotherapy, either alone or in combination with tamoxifen (TAM).
The results of a combined analysis of two trials were reported at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.The TEXT and SOFT trials were phase III randomized trials comparing the efficacy of exemestane (E) + ovarian function suppression (OFS) and TAM (T) + OFS adjuvant therapy for premenopausal ER-positive early-stage breast cancer.
A total of 5738 patients with premenopausal ER-positive early breast cancer were enrolled in the two trials, 2672 in the TEXT study and 3066 in the SOFT study.TEXT randomized patients within 12 weeks of surgery to the exemestane + ovarian function suppression group or TAM + ovarian function suppression group for 5 years (which could be combined with concurrent chemotherapy).The SOFT trial randomized patients within 12 weeks of surgery (if chemotherapy is not planned) or within 8 months of completing (neo)adjuvant chemotherapy were randomly assigned to the exemestane + ovarian function suppression group, TAM + ovarian function suppression group or TAM monotherapy group, also smelting treatment for 5 years.
The primary study endpoint was disease-free survival (DFS). Because of the low event rate, a combined analysis of the TEXT and SOFT trials was performed in 2011. By 2013, at a median follow-up of 5.7 years, a total of 514 disease-free survival events were reported in the population intention analysis for both groups. The 5-year DFS was 91.1% for patients in the exemestane + ovarian function suppression group and 87.3% for patients in the TAM + ovarian function suppression group, and the risk of recurrence was reduced by 28% in the exemestane + ovarian function suppression group. Time to breast cancer recurrence-free (BCFI) and time to distant recurrence-free (DRFI), secondary endpoints, were better in the exemestane + ovarian suppression group than in the control group in both groups. The overall survival (OS) results were similar in both groups. The incidence of grade 3 to 4 adverse events was almost identical in both groups and was similar to that previously reported for the aromatase inhibitor (AI) class of drugs.
The trial’s principal investigator (Pl), Professor Olivia Pagani, noted that TAM at 5 years has been the gold standard for adjuvant treatment of premenopausal ER-positive early-stage breast cancer for many years, and the results of the TEXT and SOFT studies suggest that exemestane + ovarian function suppression could be an alternative treatment option to TAM for this group of patients. However, we still need longer follow-up to better assess survival, side effects of long-term treatment and impact on fertility in young patients.”
1.2 Impact of obesity on the prognosis of premenopausal HR+ early breast cancer patients
Previous studies have found that obesity is associated with poor prognosis in early breast cancer; however, this association is mostly seen in ER-positive or ovarian-active breast cancers. The Early Breast Cancer Trials Collaborative Group (EBCTCG) analyzed various prognostic-related factors in 80,000 early-stage breast cancer patients from 70 clinical trials with a median follow-up of 8 years. Obesity was defined by the WHO as a body mass index (BMI) ≥30.
A clear, independent adverse effect of obesity on breast cancer mortality was found to exist only in premenopausal ER-positive disease, with a mild effect in 40,000 women with postmenopausal ER-positive disease and no effect on breast cancer mortality in 20,000 pre/postmenopausal ER-negative patients.
The study’s PI, Dr. HongchaoPan of Oxford University, pointed out that: obesity generally only increases the level of estrogen in the blood of postmenopausal women, so the findings that obesity only affects the prognosis of premenopausal women were very surprising to us, which means that the main biological mechanism by which obesity affects prognosis is not yet well understood.
2. Targeted therapy for HER2-positive early breast cancer
ALTTO is one of the important clinical trials published by ASCO in 2014 and reported by one of the principal investigators, Professor Edith A. Perez, at the conference. It is an international multicenter, randomized, open phase III clinical study in HER2-positive early-stage breast cancer. The study compared the efficacy of lapatinib monotherapy, trastuzumab monotherapy, trastuzumab sequential lapatinib and trastuzumab combined with lapatinib in combination with adjuvant therapy (1 year) in HER2-positive early breast cancer. The primary trial endpoint was DFS.
Between January 2007 and July 2011, 8381 patients from 44 countries and 946 study centers were randomly assigned to the trastuzumab monotherapy group (N=2097), the lapatinib monotherapy group (N=2100), the trastuzumab→lapatinib sequential treatment group (N=2091), or the trastuzumab+lapatinib treatment group (N=2093). After the first interim fraction showed that lapatinib monotherapy was less effective than trastuzumab monotherapy, the lapatinib monotherapy arm was discontinued on August 18, 2011, based on the recommendation of the Independent Data Monitoring Committee, and patients in this arm were then recommended for one year of trastuzumab treatment.
An interim analysis conducted in December 2013 at a median follow-up of 4.5 years showed no significant survival advantage of sequential or concurrent adjuvant lapatinib + trastuzumab over trastuzumab monotherapy for HER2-positive early-stage breast cancer, with similar 4-year DFS in the three groups: 86% in the trastuzumab group, 88% in the lapatinib + trastuzumab concurrent treatment group, and 87% in the sequential treatment group 87%. The incidence of certain adverse effects, such as diarrhea, rash and liver disease, was higher with the combination therapy compared to trastuzumab monotherapy. Another major finding of the trial was that the incidence of serious cardiac-related adverse reactions was extremely low, with congestive heart failure occurring in less than 1 percent of the ALTTO trial group, even though 95 percent of patients were treated with anthracycline-based adjuvant chemotherapy.
Investigator Professor Edith A. Perez and ASCO President Professor Clifford A. Hudis commented: Although the previous NeoALTTO study showed that patients had twice the rate of pathological complete remission (pCR) when treated with the combination of lapatinib and trastuzumab preoperatively than with trastuzumab monotherapy. We often hypothesized that the improved pCR rate with neoadjuvant therapy would effectively predict improvement in DFS and OS, and therefore substituted positive results from clinical studies of preoperative neoadjuvant chemotherapy + targeted therapy for adjuvant therapy studies.
However, the ALTTO trial did not demonstrate a survival benefit of combining anti-HER2 dual-targeted agents in adjuvant therapy. Shortcuts in drug development have been challenged, as has the recognition of surrogate endpoints in clinical studies: the US FDA has granted accelerated approval to several new drugs based on pCR, but it now appears that pCR does not equate with long-term patient prognosis. The standard regimen for adjuvant treatment of HER2-positive early-stage breast cancer remains adjuvant chemotherapy + trastuzumab for 1 year.
3.The role of bevacizumab in the adjuvant treatment of early breast cancer
The 2014 ASCO Congress reported the results of the E5103 trial. The trial selected HER2-negative breast cancers and randomly assigned 4994 patients with HER2-negative with lymph node positive or lymph node negative combined with other high-risk factors to three treatment groups according to l:2:2 for early-stage breast cancer. In addition to doxorubicin and cyclophosphamide and weekly paclitaxel, patients either received placebo (Group A: AC>T), or bevacizumab during chemotherapy (Group B: BvAC>BVT), or bevacizumab treatment during chemotherapy followed by 10 cycles of bevacizumab monotherapy (Group C: BvAC>BVT>BV). The primary endpoint was invasive-free breast cancer survival (IDFS).
The results showed that chemotherapy-related adverse events (AEs) including myelosuppression and peripheral neuropathy were similar in the three groups. The rates of greater than grade 3 hypertension, thrombosis, proteinuria, and bleeding events reported in the three groups were 2%, 8%, and 11%, respectively. the cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0%. approximately 24% of patients in group B and 55% of patients in group C discontinued bevacizumab therapy before completion of the trial program.
The median follow-up was 47.5 months, with a total of 430 IDFS events in groups A, B, and C. The 5-year IDFS was similar in the three groups, at 77%, 76%, and 80%, respectively. The study showed that adding bevacizumab to adjuvant therapy with anthracyclines and paclitaxel did not improve IDFS or OS in high-risk HER2-negative breast cancer patients. application of bevacizumab did increase adverse events, resulting in a high rate of early discontinuation events with bevacizumab.
Whether in HER2-positive breast cancer (BETH study, 3509 patients, adjuvant chemotherapy/trastuzumab +/- bevacizumab), in TNBC (BEATRICE study, 2591 patients, adjuvant chemotherapy +/- bevacizumab), and in HER2-negative breast cancer with high-risk factors (E5103 study), the addition of bevacizumab to adjuvant chemotherapy Neither study increased DFS or OS benefit. Furthermore, all of these studies found a significantly higher incidence of grade 3 to 4 toxicity in the bevacizumab group and a higher rate of treatment discontinuation due to toxicity. The evidence to date suggests that bevacizumab is not suitable for adjuvant breast cancer treatment.