Key takeaways for India from 8 studies presented at SABCS 2018: Dr. Vishwanath & Dr. Vinayak
M3 India Newsdesk Dec 27, 2018
Noted Medical Oncologists, Dr. Vinayak Maka and Dr. Vishwanath Sathyanarayanan choose 8 major India-relevant studies from the recent San Antonio Breast Cancer Symposium 2018, summarising them and providing their expert take on each.
KATHERINE trial
Dr. Vishwanath: In this phase III trial, adjuvant T-DM1 improves disease-free survival (DFS) in patients with HER2 positive early-stage breast cancer with residual disease after NACT. However, in the Indian setting, cost constraints may be an issue. Moreover, if T-DM1 is used in the adjuvant scenario, this reduces options for the patient at the time of recurrence/metastasis.
Dr. Vinayak: Neoadjuvant therapy can be used to identify patients at increased risk for recurrence based on less than optimal response to standard neoadjuvant therapies who can benefit by switching to ado-trastuzumab emtansine. Other than financial implications, this option can be practice-changing and be the first kind of response-adapted treatment escalation.
Study: Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: primary results from KATHERINE
This was an open-label study of 1,486 patients with HER2-positive early-stage breast cancer who received neoadjuvant chemotherapy plus HER2-targeted therapy that included a taxane and trastuzumab, followed by surgery. All patients had residual invasive disease in the breast or axillary lymph nodes. Within 12 weeks of surgery, patients were randomly assigned 1:1 to T-DM1 (3.6 mg/kg IV every three weeks) or trastuzumab (6 mg/kg IV every three weeks), for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS).
IDFS events (events of disease recurrence or death without recurrence) occurred in 12.2% of patients in the T-DM1 arm, compared with 22.2% in the trastuzumab arm. Secondary efficacy endpoints of disease-free survival and distant recurrence-free interval also demonstrated clinically meaningful reduction in events with T-DM1 relative to trastuzumab. Additional follow-up will be needed to determine the effect of adjuvant T-DM1 on survival.
CIBOMA/2004-01_GEICAM/2003-11 study
Dr. Vinayak: After results of the CREATE-X trial, treatment-response-based escalation of adjuvant chemotherapy with oral capecitabine is slowly but steadily catching up in our practice. These results show triple-negative breast cancer (TNBC) population is heterogeneous and with careful selection of subgroup by IHC for nonbasal TNBC better outcomes can be achieved.
Dr. Vishwanath: This trial was not well-powered and hence the conclusions may not be practice changing. Oncologists in India could use adjuvant capecitabine in TNBC based on the CREAT-X trial results with reasonable success. Capecitabine is bioeconomical and still an excellent option in the adjuvant setting for TNBC patients.
Study: Efficacy results from CIBOMA/2004-01_GEICAM/2003-11 study: A randomized phase III trial assessing adjuvant capecitabine after standard chemotherapy for patients with early triple negative breast cancer
Dr. Martín and fellow researchers enrolled 876 patients with early-stage triple-negative breast cancer who previously had surgery and chemotherapy in the study, randomising them to either eight cycles of capecitabine or observation.
Disease-free survival was not significantly improved in early-stage triple-negative breast cancer patients who received capecitabine after completing surgery and standard chemotherapy. A sub-group analysis on 248 patients with non-basal-like disease, which was defined by immunohistochemistry revealed that these patients were 49% less likely to have a disease event and 52% less likely to die when compared to patients randomised to the observation group.
Adjuvant chemotherapy in TNBC
Dr. Vishwanath: Several studies have indicated that there is a high risk of systemic relapse in TNBC patients during the first two years. In view of micrometastatic disease, delay in adjuvant treatment increases the risk of recurrence. This retrospective study re-emphasises the fact that early initiation of adjuvant treatment reduces the risk of recurrence.
Dr. Vinayak: this retrospective study gives target timelines to adhere for in TNBC while starting adjuvant chemotherapy for achieving better outcomes.
Study: Impact of the delayed initiation of adjuvant chemotherapy in the outcomes of triple negative breast cancer
The recent retrospective study presented at the 2018 San Antonio Breast Cancer Symposium emphasised the importance of initiating adjuvant chemotherapy treatment as soon as possible following surgery in order to achieve the most effective outcome for patients with triple negative breast cancer.
Specifically, the study indicated that patients who began adjuvant chemotherapy within 30 days after surgery had significantly reduced risks for relapse and death compared to those who initiated treatment after 30 days.
They found that delays in adjuvant chemotherapy greater than 30 days after surgical intervention led to an increased risk of more than 90% for disease recurrence and death. Moreover, this risk is further amplified if treatment is postponed for 60 days.
PHARE trial
Dr. Vinayak: Adjuvant trastuzumab of one year has been widely contested since the last ASCO meet where PERSEPHONE data was presented. This trial shows the need to refine population who will need de-escalation of treatment duration.
Dr. Vishwanath: This trial failed to show that 6 months was non-inferior to 12 months of adjuvant trastuzumab in HER2 positive EBC. Moreover, the disease-free survival, overall survival, and metastasis-free survival were better in the longer duration trastuzumab arm. Clinicians should continue to recommend 1 year of adjuvant of trastuzumab in HER2+ EBC considering the aggressive nature of such cancers.
Study: PHARE randomized trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer
The PHARE trial (NCT00381901) was a randomised, controlled, multicentre study in patients with HER2-positive EBC who had received at least four cycles of (neo)adjuvant chemotherapy were eligible. Randomisation (1:1) of patients to the control arm (12 months of trastuzumab) or the experimental arm (six months of trastuzumab) used a minimisation algorithm that stratified patients based on concomitant or sequential trastuzumab administration with chemotherapy, estrogen receptor (ER) status, and treatment centre.
The primary objective was to compare disease-free survival (DFS). An absolute loss of 2% in DFS in the experimental arm was defined as the noninferiority margin (1.15 in relative terms), which required accrual of 3,400 patients to reach 1,040 DFS events for 80% power at an alpha of 5%. Despite long follow-up, the shorter treatment duration failed to show noninferiority to the standard 12-month schedule (HR, 1.28; 95% CI, 1.05-1.56; P = .29), although cardiotoxicity was lower.
N-SAS BC 05 trial: AERAS study
Study: A prospective randomized multi-center open-label phase III trial of extending aromatase-inhibitor adjuvant therapy to 10 years - Results from 1697 postmenopausal women in the N-SAS BC 05 trial: Arimidex extended adjuvant randomized study (AERAS)
Extending adjuvant endocrine therapy with an aromatase inhibitor to 10 years led to significant improvement in disease-free survival (DFS) and distant disease-free survival (DDFS) in postmenopausal women with hormone receptor-positive (HR-positive) breast cancer.
Patients randomised to receive an additional 5 years of endocrine therapy had a DFS of 91.9% at 5 years post-randomisation as compared with 84.4% among patients who stopped endocrine treatment after 5 years. However, the improved DFS did not translate into an improvement in overall survival (OS).
Dr. Vishwanath: DFS is an important endpoint in the adjuvant setting. Improvement in DFS by 7.5% with 10 vs. 5 years of AIs is a significant benefit for patients with HR+ HER2- non-metastatic breast cancer in the GS3-04 trial. The meta-analysis showed that extended AI treatment translates into further reduction in recurrence if preceded by tamoxifen.
Dr. Vinayak: Subgroup analysis did not identify any group of patients who did not benefit from extended endocrine therapy in the Japanese study but metanalysis showed that the benefits of extended therapy differed according to type or prior therapy, with a larger reduction in the risk of recurrence when the AI was preceded by tamoxifen. Ideally, patients with node-positive disease should continue an aromatase inhibitor for 10 years.
EBCTCG meta-analysis
Study: Effects of prolonging adjuvant aromatase inhibitor therapy beyond five years on recurrence and cause-specific mortality: an EBCTCG meta-analysis of individual patient data from 12 randomised trials including 24,912 women
A meta-analysis of 11 randomised trials of extended AI treatment after prior endocrine therapy. The results showed that the benefits of extended therapy differed according to type or prior therapy, with a larger reduction in the risk of recurrence when the AI was preceded by tamoxifen.
IMpassion130
Dr. Vinayak: Search for universal and single immune biomarker for checkpoint inhibitor remains an enigma. Until now there have been either tumour agnostic biomarkers like MSI or ligand biomarkers. Eventually, these biomarkers will help in predicting patients who will benefit from immunotherapy.
Dr. Vishwanath: Based on the exploratory analysis of this phase 3 trial, the authors concluded that the PD-L1 IC was the most robust predictive biomarker for selecting patients who may possibly benefit with this combination therapy. Since Atezolizumab is expensive, it may be reasonable to choose patients for this treatment based on the PD-L1 IC results. Most patients who were positive for PDL1 were also positive for PD-L1 ICs.
Study: IMpassion130: Efficacy in immune biomarker subgroups from the global, randomized, double-blind, placebo-controlled, phase III study of Atezolizumab + nab-paclitaxel in patients with treatment-naïve, locally advanced or metastatic triple-negative breast cancer
The Impassion 130 study was a phase III study that examined the efficacy of combining Atezolizumab (anti-PD-L1) with nab-paclitaxel as first-line therapy for patients with metastatic triple-negative breast cancer (TNBC). The control group received a placebo in combination with nab-paclitaxel. As endpoints for the study, biomarkers, such as PD-L1 on tumour cells, BRCA1/2 mutational status, and ER/PR/HER2 mutational status, were examined.
The authors found that there was consistency between local and central ER/PR/HER2 testing. In addition, PD-L1 IC was shown to be the most prognostic biomarker for choosing untreated mTNBC patients who would benefit from the combination of Atezolizumab and nab-paclitaxel.
EORTC AMAROS trial
Dr. Vishwanath: Though both modalities are equivalent, the increased risk of second primary cancers with axillary radiotherapy has to be kept in mind.
Dr. Vinayak: After positive sentinel node, with both modalities being non-inferior we could avoid long-term limb morbidity in early breast cancer patients by sparing axillary dissection.
Study: Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: 10 year follow up results of the EORTC AMAROS trial (EORTC 10981/22023)
Patients with early-stage breast cancer who had cancer detected in a sentinel lymph node biopsy had comparable 10-year recurrence and survival rates following either axillary radiotherapy or axillary lymph node dissection, according to data from the randomised, phase III AMAROS clinical trial presented by Rutgers et al. at the 2018 San Antonio Breast Cancer Symposium.
Neither distant metastasis-free survival nor overall survival was significantly different between the two treatment arms. A significantly greater proportion of patients assigned to axillary radiotherapy went on to develop a second primary cancer, compared with patients assigned to axillary lymph node dissection—11.0% vs 7.7%.
Lisinopril/carvedilol in HER2-positive breast cancer
Dr. Vinayak: Trastuzumab and Anthracyclines are most beneficial in the treatment of breast cancer and cardiotoxicities erode benefit of increased survival. These cardioprotective interventions will help us to offer effective therapies without long-term cardiac complications.
Dr. Vishwanath: This is a very interesting and practically relevant study. By adding beta blockers and ACE inhibitors in patients receiving anthracyclines and trastuzumab, the risk of cardiotoxicity reduces. This will eventually translate into better patient outcome as dose intensity is maintained.
Study: A randomized community-based trial of lisinopril or carvedilol for the prevention of cardiotoxicity in patients with early stage HER2-positive breast cancer receiving adjuvant trastuzumab
Trastuzumab is a critical component of therapy for patients with early-stage HER2+ breast cancer. However, cardiac toxicity is one of the side effects of trastuzumab. Cardiac side effects are particularly evident in patients who also receive anthracyclines, leading to more rigorous monitoring and oftentimes, discontinuation of trastuzumab.
In this study, researchers hypothesise that prophylactic use of beta-blockers (BB) or angiotensin-converting enzyme (ACE) inhibitors may alleviate the cardiac side effects associated with trastuzumab therapy. Researchers found that in HER+ breast cancer patients taking both trastuzumab and an anthracycline, prophylactic use of both lisinopril and carvedilol reduced cardiotoxicity.
Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.
Dr. Vishwanath Sathyanarayan is a Medical Oncologist from Apollo Hospitals, Bangalore with a fellowship from MD Anderson Cancer Center.
Dr. Vinayak Maka is a Senior Medical Oncologist who teaches and practice at the MS Ramaiah Medical College and the HCG MSR Cancer Centre, Bangalore.
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