In this issue of ONCOLOGY, von Minckwitz and colleagues review the current standards for neoadjuvant therapy for HER2-positive breast cancer. Until recently, neoadjuvant therapy was primarily used to treat larger, more aggressive tumors with the goal of improving the rate of breast-conserving surgery. Important to this approach were data from phase III studies demonstrating similar disease-free and overall survival regardless of whether chemotherapy was given before or after surgery.[1,2] Longer follow-up demonstrated improved outcome in patients with no residual invasive cancer in the breast (pathologic complete remission [pCR])[3]; later trials found the lack of residual invasive disease in breast and axillary nodes to be an even better predictor of subsequent outcome.[4,5] Subsequent studies first demonstrated a marked improvement in pCR with the addition of trastuzumab(Drug information on trastuzumab) (Herceptin),[6] then associated both pCR and trastuzumab administration with improved disease-free survival (DFS).[7] Combined HER2 blockade with additional targeted biologic therapies has further improved response.[8-10]
It may not be appropriate, nor always considered standard, to recommend neoadjuvant chemotherapy for all patients for whom adjuvant therapy was recommended before surgery. Indeed, tumor size and nodal status play a role, as do hormone receptors, in determining the appropriate extent of adjuvant therapy. For smaller tumors (but those greater than 1 cm), extensive chemotherapy may not be indicated. Perhaps understanding individual prognosis based on extent of response is sufficient reason to start with neoadjuvant therapy, but does this knowledge help with subsequent management? Although response clearly correlates with outcome, it does not currently allow selection of more effective therapy. Additional therapy targeted to HER2 or pathways responsible for resistance to HER2-targeted therapy may help to change this in the near future, making neoadjuvant therapy the standard for all but the smallest tumors, as Dr. von Minckwitz suggests.
Tumor heterogeneity may play a role in response to neoadjuvant therapy in patients with HER2-positive disease. In a small retrospective study, about one-third of patients with residual tumor following neoadjuvant trastuzumab-based therapy no longer had evidence of HER2 gene amplification; loss of HER2 was associated with worse relapse-free survival.[11] It has long been hoped that tumor biomarkers will guide therapy in the future. Unfortunately, a detailed analysis of tumor samples from patients enrolled in the neoadjuvant NeoSphere trial failed to identify markers capable of predicting improved response to dual antibody blockade either with or without chemotherapy, and there are no data yet on correlative studies from the neoadjuvant trials with lapatinib (Tykerb).[8,12]
There is ongoing controversy not only about the importance of overlapping HER2-targeted therapy with anthracyclines, based on encouraging synergy in the preclinical setting,[13] but also about the importance of duration of chemotherapy[14] before surgery. However, this discussion has been based primarily on rates of pCR, which may not have the same implications for outcome in the 50% of patients with HER2-positive disease whose tumors retain expression of the estrogen receptor.[15] Recent studies, outlined in the current review, have reported lower pCR rates in tumors that are both HER2- and hormone receptor–positive regardless of treatment.[8-10] However, 4-year follow-up of the combined NCCTG N9831 and NSABP B-31 trials demonstrated improved DFS in patients receiving trastuzumab with triple-positive vs hormone receptor–negative disease (89.4% vs 81.6%, respectively).[16] In this review, von Minckwitz suggests by cross-trial comparison to the NeoALTTO trial that the higher pCR rates seen in GeparQuinto are due to the combination of trastuzumab with epirubicin(Drug information on epirubicin), as well as longer duration of therapy. Do current data support that assertion?
The recently presented three-arm TRYPHAENA trial was designed primarily to evaluate the toxicity of combined anti-HER2 blockade with anthracycline or carboplatin(Drug information on carboplatin) in the neoadjuvant setting, and also to assess potential differences in efficacy by pCR rates.[17]A total of 225 women with centrally confirmed HER2-positive tumors of at least 2 cm in size were randomized to one of three arms. Arms A and B received FEC-100 (fluorouracil [5-FU] at 500 mg/m2, epirubicin at 100 mg/m2, and cyclophosphamide(Drug information on cyclophosphamide) at 600 mg/m2) for 3 cycles followed by docetaxel(Drug information on docetaxel) (at 75 mg/m2, escalating to 100 mg/m2 as tolerated) for 3 cycles, and were randomized to start the combination of pertuzumab and trastuzumab with cycle 1 of FEC or with cycle 1 of docetaxel. Arm C received docetaxel (at 100 mg/m2) and carboplatin (AUC 6) for 6 cycles with concurrent pertuzumab and trastuzumab. Surgery was planned to follow the last cycle of chemotherapy, then trastuzumab was given to complete 1 year of therapy. The mean change in left ventricular ejection fraction was similar in the three arms, with rare symptomatic events. Pathologic complete response, regardless of definition, was similar across the three arms with only a slight numerical decrease in arm B despite the shorter exposure to targeted therapy and the lack of overlap with anthracycline. A greater numerical difference favoring arms A and C was seen in the patients with hormone receptor–negative disease, but the numbers are too small for these data to be conclusive.
The American College of Surgeons Oncology Group (ACOSOG) Z1041 study, now closed to accrual, is a phase III trial that randomized about 270 women with HER2-positive early stage breast cancer to receive neoadjuvant FEC-75 followed by weekly paclitaxel(Drug information on paclitaxel) with trastuzumab or weekly paclitaxel with trastuzumab followed by FEC-75 with trastuzumab. All patients received trastuzumab after surgery for a 1-year course. The primary endpoint of this trial is pCR, but it asks a sequencing question as well as addressing the combination of anthracycline and trastuzumab. Results should be available in 2012 and, together with TRYPHAENA, should help to determine the best “control” arm to which newer strategies should be compared.
What is perhaps most fascinating, and particularly well highlighted in HER2-positive disease, is the ability of response to neoadjuvant therapy to predict subsequent results in the adjuvant or metastatic setting. Improved pCR rates with the combination of pertuzumab, trastuzumab, and docetaxel in the NOAH trial[15] correlated with recent data demonstrating remarkably improved progression-free survival and an early suggestion of overall survival benefit with the same combination in the first-line metastatic setting CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial.[18] Inferiority and increased toxicity of the lapatinib-alone arms in the NeoALTTO and GeparQuinto trials[9,10] correlated with early closure due to futility in the ongoing adjuvant ALTTO trial.
These data suggest response to neoadjuvant therapy could be used as a mechanism for drug approval, and certainly to inform the design of clinical trials leading to early approval of effective therapy. There is currently a wealth of emerging riches for the treatment of HER2-positive breast cancer, but the speed of drug development is still maddeningly slow, with agents such as pertuzumab only now being tested in early-stage disease (the APHINITY trial) directed toward registration and trastuzumab DM-1 still awaiting definitive data in the metastatic setting.[19] Multiple other agents that inhibit steps in the PI3-kinase/mTOR (mammalian target of rapamycin) pathway are under investigation. The multicenter Foundation for the National Institute of Health–sponsored neoadjuvant ISPY2 trial (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) represents a novel investigative approach and an important step in designing successful and relevant clinical trials. This trial, which tests a series of novel agents based on tumor biology in combination with standard chemotherapy, aims to speed the process of drug development while identifying biomarkers for response.
Financial Disclosure: Dr. Rugo receives research support (to UCSF) from Genentech/Roche, Pfizer, and Bayer/Onyx.
