By Chau T. Dang, MD, Pedram Razavi, MD, PhD, Sarat Chandarlapaty, MD, PhD, and Shanu Modi, MD
May 25, 2019
The discovery of trastuzumab has been revolutionary in the treatment of HER2-positive breast cancer, both in the metastatic and early-stage settings.1-6 This cannot be disputed. In the early-stage setting, the addition of trastuzumab to standard chemotherapy has led to a 50% gain in disease-free survival and a 30% improvement in overall survival.3-5 Subsequently, trials enrolling patients deemed to have high-risk HER2-positive breast cancer demonstrated that extended therapy with neratinib (tyrosine kinase inhibitor against HER1/HER2/HER4) given sequentially after adjuvant trastuzumab, or the combination of pertuzumab given concurrently with trastuzumab, led to small incremental gains, particularly in patients with hormone receptor–positive cancer and node-positive disease, respectively.7,8 However, the magnitude of benefit was not nearly as significant as that observed with trastuzumab in the initial trials, until the release of KATHERINE.9
In this randomized study, reviewed in this issue of The ASCO Post, patients with residual disease after neoadjuvant chemotherapy were randomly assigned to adjuvant trastuzumab emtansine (T-DM1) or trastuzumab alone, both for 14 cycles. T-DM1 is an antibody-drug conjugate where the antibody is trastuzumab covalently linked to the cytotoxic agent DM1. Patients who received T-DM1 achieved a 50% improvement in 3-year invasive disease–free survival over those who received trastuzumab alone (77.0% vs 88.3%, hazard ratio = 0.50, 95% confidence interval = 0.39–0.64, P < .001). This is particularly striking, given only 71.4% of patients completed all 14 cycles of T-DM1.
Based on these results, T-DM1 is considered a new standard treatment for those with residual disease after neoadjuvant chemotherapy. The results of KATHERINE echo those of the CREATE-X trial. In the CREATE-X trial, patients with HER2-negative breast cancer who had residual disease after standard neoadjuvant chemotherapy were randomly assigned to capecitabine or not; the study revealed a significant benefit in favor of more chemotherapy.10
Who Benefits From T-DM1?
Results from the KATHERINE trial raise some interesting questions: Should all patients with HER2-positive early-stage breast cancer receive neoadjuvant chemotherapy or adjuvant T-DM1 if residual disease is found? If patients are unable to complete T-DM1, should they be given standard trastuzumab alone (as per KATHERINE) or trastuzumab/pertuzumab? Although the 3-year invasive disease–free survival of 88.3% is good with T-DM1, is it good enough, or is there room for improvement?
So, for patients with stage I HER2-positive breast cancer and candidates for breast conservation, delivering neoadjuvant chemotherapy has limited value and is unlikely to change the planned surgery. Moreover, updated results from the APT trial, an adjuvant study comprising largely patients with stage I HER2-positive breast cancer, demonstrated an impressive 7-year disease-free survival of 93% with paclitaxel/trastuzumab therapy.6 As such, it is highly unlikely that further adjuvant treatment with T-DM1 would offer substantial improvement to these already excellent outcomes, particularly given the risk of additional neurotoxicity, as reported in KATHERINE.9
Who Benefits From Pertuzumab?
As for those who cannot complete 14 cycles of adjuvant T-DM1, if pertuzumab is available, it is reasonable to complete 1 year of anti-HER2 therapy with the trastuzumab/pertuzumab combination. Although T-DM1 is now a new standard in those with residual disease, we still do not have direct evidence that T-DM1 is superior to trastuzumab/pertuzumab. In fact, it is noteworthy to mention that trastuzumab/pertuzumab has generally been superior to control, but T-DM1–based treatment has not in some studies.13-15 In APHINITY, although the addition of pertuzumab to trastuzumab led to a modest gain in 3-year invasive disease–free survival in the intention-to-treat population, it was more significant in those with node-positive disease in the preplanned analysis.8
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So, it appears that the addition of pertuzumab is beneficial in those with a high burden of disease, such as those with metastatic disease and node-positive early-stage cancer. Thus, when patients are unable to complete T-DM1, completing adjuvant therapy with trastuzumab/pertuzumab in those with high-risk breast cancer, such as those with a high burden of disease (ie, node-positive),
Future Treatment Possibilities
Finally, as we look to the future and improving upon the advances we’ve already made, perhaps there will be a role for other novel agents in these high-risk patients with residual disease, such as immunotherapy and other next-generation therapies (ie, selective tyrosine kinase inhibitors, cyclin-dependent kinase 4/6 inhibitors, and other potent antibody-drug conjugates). An even more innovative approach would be to evaluate T-DM1 and/or other novel agents in patients based on circulating tumor DNA after neoadjuvant chemotherapy, including patients with conventionally determined pathologic complete response, as a subset of these patients are still at risk for distant recurrence. ■
Dr. Dang is a medical oncologist practicing at Memorial Sloan Kettering Cancer Center (MSK), New York, New York. Dr. Razavi is a medical oncologist and Instructor in Medicine at MSK. Dr. Chandarlapaty is Assistant Attending Physician and Laboratory Head, Human Oncology and Pathogenesis Program at MSK. Dr. Modi is a medical oncologist practicing at MSK.
DISCLOSURE: Dr. Dang has received institutional research funding from Genentech/Roche and Puma Biotechnology; and is a consultant/advisor for Roche/Genentech, Puma, and Daiichi Sankyo. Dr. Razavi has received institutional research funding from GRAIL and Illumina Dr. Chandarlapaty is a consultant/advisor for Sermonix Pharmaceuticals, Novartis, Context Therapeutics, Lilly, Revolution Medicine, and BMS; has received institutional research funding from Novartis, Daiichi Sankyo, Sanofi, Lilly, and Genentech; and travel/accommodations/expenses from Novartis, Sun Pharma, and BMS. Dr. Modi is a consultant/advisor for Daiichi Sankyo; is on the speakers bureau for Genentech; and has received funding from Roche/Genentech, Novartis, Seattle Genetics, Synta, and Daiichi Sankyo.
1. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001.
2. Marty M, Cognetti F, Maraninchi D, et al: Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol 23:4265-4274, 2005.
3. Perez EA, Romond EH, Suman VJ, et al: Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: Planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 32:3744-3752, 2014.
Read more Post-neoadjuvant treatment and the management of residual disease in breast cancer: state of the art and perspectives
4. Slamon DJ, Eiermann W, Robert NJ, et al: Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab in HER2-positive early breast cancer. 2015 San Antonio Breast Cancer Symposium. Abstract S5-04. Presented December 11, 2015.
5. Cameron D, Piccart-Gebhart MJ, Gelber RD, et al: 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: Final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 389:1195-1205, 2017.
6. Tolaney SM, Guo H, Pernas S, et al: Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast Cancer. J Clin Oncol. April 2, 2019 (early release online).
7. Chan A, Delaloge S, Holmes FA, et al: Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17:367-377, 2016.
8. von Minckwitz G, Procter M, de Azambuja E, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 377:122-131, 2017.
9. von Minckwitz G, Huang, CS, Mano MS, et al: Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380:617-628, 2019.
10. Masuda N, Lee SJ, Ohtani S, et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376:2147-2159, 2017.
11. Schneeweiss A, Chia S, Hickish T, et al: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24:2278-2284, 2013.
12. Swain SM, Ewer MS, Viale G, et al: Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): A phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol 29:646-653, 2018.
13. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012.
14. Perez EA, Barrios C, Eiermann W, et al: Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: Primary results from the phase III MARIANNE study. J Clin Oncol 35:141-148, 2017.
15. Hurvitz SA, Martin M, Symmans WF, et al: Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): A randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 19:115-126, 2018.
— Update: 16-03-2023 — cohaitungchi.com found an additional article Post-neoadjuvant treatment and the management of residual disease in breast cancer: state of the art and perspectives from the website www.ncbi.nlm.nih.gov for the keyword treatment for residual breast cancer.
Rationale for adapting NAT according to clinical response
Imaging studies and physical examination can be performed during NAT to obtain an early assessment of response. The objective of this strategy is to identify patients who are not responding to treatment, providing an opportunity for these individuals to receive agents with different mechanisms of action, in an attempt to overcome resistance. Studies investigating this strategy aimed to improve the pCR rates after NAT and were the pioneers for the development of the post-neoadjuvant treatment rationale.26 Two main randomized trials have investigated the benefit of modifying ongoing NAT after an early assessment of clinical response.
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In the GeparTrio trial, 2072 patients with operable or locally advanced BC had response assessments after two cycles of TAC (docetaxel 75 mg/m², doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m² at D1, every 3 weeks). A total of 622 patients who did not present a response according to breast clinical examination and ultrasound (defined as a decrease in tumor size ⩾50%), were randomized 1:1 to proceed with either four cycles of TAC or change to four cycles of NX (vinorelbine 25 mg/m² D1 and D8, capecitabine 1000 mg/m² twice a day on D1–D14, every 3 weeks). Compared with the control arm assigned to TAC, patients who were switched to NX failed to achieve increased clinical response rates (50.5% versus 51.2%) or pCR rates (6% versus 5.3%).27 Interestingly, updated results from this trial demonstrated a disease-free survival (DFS) benefit for early nonresponders assigned to TAC-NX versus those who continued TAC (hazard ratio [HR] 0.59; p = 0.001), although this was a secondary endpoint of the study.28
In the study by Smith and colleagues, 162 locally advanced BC patients started NAT with four cycles of CVAP (cyclophosphamide 1000 mg/m², doxorubicin 50 mg/m² and vincristine 1.5 mg/m² at D1, and prednisolone 40 mg/day D1–D5, every 21 days for four cycles), with the responders (clinical response assessed by physical examination) being randomized to four additional cycles of CVAP or four cycles of docetaxel 100 mg/m2 every 21 days, while the nonresponders were switched to four cycles of docetaxel. A 55% clinical response rate was observed for patients who were not responding to CVAP and changed to docetaxel. However, the pCR rate in this group was only 2%, demonstrating that the switch to docetaxel was unable to increase pCR rates in patients that were not responding to an anthracycline-based chemotherapy.29
These trials demonstrated that the chances of achieving a pCR by chemotherapy modification according to response assessments during NAT are modest. The benefit of this strategy has not been confirmed in clinical trials and it is not routinely used. However, these studies have modified treatment according to clinical response assessed by physical examination or ultrasound, which is not precise and presents a poor correlation with pathological response.30,31 The interest in overcoming BC resistance by offering additional treatments with different mechanisms of action remained, but instead of relying on clinical response, a reasonable alternative would be to focus on the patients that do not achieve a pCR, thereby offering additional treatment for the individuals with demonstrated treatment resistance and a high risk of recurrence.