TCH Regimen

Abstract: A 60-year-old Caucasian female presented with stage IIA (T2N0M0) estrogen- and progesterone-negative and HER2-positive breast cancer. She was started on an adjuvant chemotherapy regimen of docetaxel, carboplatin, and trastuzumab (TCH). She tolerated the first two cycles of the TCH regimen well. However, 3–4 days after the third and fourth cycles, she developed acute pancreatitis. Elevated pancreatic enzymes and abdominal computed tomography (CT) imaging findings confirmed the diagnosis of acute pancreatitis. Common causes of pancreatitis were ruled out. Given the time course it was assumed that the chemotherapy was the cause of pancreatitis in our patient. The patient did not receive any further docetaxel and carboplatin chemotherapy but continued on adjuvant trastuzumab alone for a planned duration of 1 year without any recurrence of acute pancreatitis.

Abstract: BACKGROUND: The neoadjuvant chemotherapy in HER2-positive breast cancer consists of a chemotherapy backbone and HER2-directed therapy. The increase in cardiotoxicity by the use of trastuzumab with an anthracycline-based regimen has led to the use of nonanthracycline-based alternative regimens. The docetaxel, carboplatin, and trastuzumab (TCH) are one such regimen. The efficacy and toxicity of this regimen have not been widely studied in Indian patients. AIMS: This retrospective study aims to evaluate the efficacy and toxicity of neoadjuvant TCH regimen in locally advanced and oligometastatic HER2-positive breast cancer in Indian patients. METHODOLOGY: The hospital records between January 2014 and December 2016 were reviewed to identify patients with locally advanced and oligometastatic HER2-positive breast cancer treated with uniform 3-weekly neoadjuvant chemotherapy protocol-containing docetaxel (75 mg/m2), carboplatin (AUC = 6), and trastuzumab (8 mg/kg loading followed by 6 mg/kg) (TCH). The primary outcome was the pathologic complete response (pCR), which was defined as an absence of invasive and noninvasive cancer in breast or lymphnode. RESULTS: Thirty-two patients with mean age 46 years met our inclusion criteria, of these 24 patients had locally advanced breast cancer, and eight patients had oligometastatic breast cancer. 13 (40.6%) patients had hormone-positive breast cancer. The objective response rate as assessed clinically was 100%, and pCR rate was 36.3%. The patients with oligometastatic breast cancer also showed a good response to chemotherapy with three patients showing pCR and four patients showing resolution disease at metastatic sites. The patients experienced very few Grade III/IV toxicities, and no patient had clinical congestive heart failure. CONCLUSION: The TCH protocol is an efficacious neoadjuvant chemotherapy regimen for locally advanced and oligometastatic breast cancer and is safe and well tolerated in this population.

Abstract: Considering the clinical benefit of trastuzumab in advanced breast cancer, fi ve prospective adjuvant randomized trials have recently been completed and early results have been published Two of them, (NSABP-B31 and NCCTG N9831), employed anthracycline-containing regimens with sequential paclitaxel, with or without trastuzumab The third study, HERA trial, randomized patients after adjuvant chemotherapy into an observational arm, one or two years of trastuzumab Results of these studies, after a median follow up of 2-3 years confirm a DFS and OS benefit for the experimental arms The worst rate of cardiotoxicity, in terms of incidence of CHF, with the use of trastuzumab and anthracycline based regimens was 41% in the trastuzumab arm of the NSABP-B31 trial Among the fi ve trastuzumab trials, two, BCIRG 006 and FinHer, employed docetaxel-based regimens The innovative BCIRG 006 trial compared ACdocetaxel (T) with two trastuzumab-containing regimens, ACTH, and a non-anthracycline-containing regimens, TCH, with a clear advantage in DFS for both trastuzumab arms Data from the second interim analysis indicate that, in the subgroup of patients without co-amplification of topoisomerase 2 (TOPO-2), the arm without trastuzumab (ACT) showed a DFS significantly poorer that in the other arms; moreover, if we consider the lower toxicity of TCH regimen in comparison with anthracycline-containing arms, the innovative statements offered by BCIRG 006 trial appear evident, and these findings opened an important question about the consolidated employment of anthracyclines in adjuvant settingThe FinHer trial was a small trial testing a short course of trastuzumab (9 weeks) concomitantly with a chemotherapy including docetaxel, and there was a significant advantage in DFS for the trastuzumab based arms, without relevant toxicity and without any cardiotoxicity Although data from all trastuzumab adjuvant trials, and without particulary from BCIRG-006 and FinHer trials, appear very intriguing, further follow-up is required

Abstract: TO THE EDITOR: Press et al 1 concluded that “TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy.” I do not believe that this conclusion is justified on the basis of the data they examined. To evaluate whether a marker is predictive for benefit from a drug, one should compare (either prospectively or by using archived specimens from a previous trial) outcomes for patients who were randomly assigned to receive a regimen containing the drug or the same regimen not containing the drug, and one should examine how this treatment effect (ie, hazard ratio) depends on marker status. 2 The studies Press et al 1 examined did not permit such an evaluation. The closest one could come to a direct analysis of whether TOP2A amplification is a predictive marker of anthracycline effectiveness was an analysis that Press et al did not comment on. In trial BCIRG-006 of the Breast Cancer International Research Group, patients with HER2amplified tumors were randomized to receive ACT (doxorubicin, cyclophosphamide, docetaxel), ACTH (ACT plus trastuzumab), or TCH (docetaxel, carboplatin, trastuzumab). A comparison of the ACTH regimen with the TCH regimen isolates the value of the anthracycline relative to carboplatin with both in the presence of trastuzumab. In Figure 3 of the article by Press et al, 1 outcomes for these two regimens seem equivalent both forTOP2A-amplified and forTOP2Aunamplified tumors. In the patients with amplified tumors, there were 35 events on treatment with ACTH compared with 42 events on treatment with TCH; in the patients with unamplified tumors, there were 87 events on ACTH compared with 92 on TCH. Consequently, on the basis of the only relevant direct randomized comparison of anthracycline use available in the authors’ data, there is no evidence that the efficacy of the anthracycline depends on TOP2A status. The authors base their conclusions on indirect evidence. In both the BCIRG-006 adjuvant study and the H0648g, the original trastuzumab metastatic disease licensing study, the investigators compared an anthracycline regimen not containing trastuzumab with the same anthracycline regimen administered with trastuzumab. They noted that trastuzumab did not seem to improve outcome in the small subset of patients with amplifiedTOP2A but that it did improve outcome for patients without TOP2A amplifications. The significant interaction in Table 3 is for the incremental effect of trastuzumab, not as stated for the incremental effect of anthracycline. They interpret this variation in trastuzumab treatment effect as indicating that the anthracycline is more effective in patients withTOP2A amplifications. The fact that trastuzumab is ineffective in patients with TOP2A amplifications receiving an anthracycline-based regimen does not necessarily mean that the anthracyclines are effective in that subset. Patients with large amplifications not focused on the HER2 gene may have tumors driven by genes other than HER2 and thus be less responsive to HER2 inhibition. The conclusion is also based on a limited number of events involved. This type of indirect analysis does not provide a strong level of evidence according to the scale introduced by Simon et al 2 for evaluating the medical utility of predictive biomarkers. The pragmatic question of importance is which patients should be considered good candidates for anthracycline-based regimens. Previous studies have indicated that patients without HER2-amplified tumors are unlikely to benefit from such regimens. 3,4 The data for BCIRG-006 indicates that, for patients with HER2-amplified tumors who will receive trastuzumab, the docetaxel/carboplatin regimen seems as effective as the ACT regimen, regardless of TOP2A status. This leaves little room for the use of anthracyclines and no reason for the measurement of TOP2A amplification status. The data for BCIRG-006 suggests that patients with amplified HER2 and TOP2A might do as well on ACT as on ACTH—ie, they might not benefit from trastuzumab in the presence of ACT. This conclusion of therapeutic equivalence requires independent confirmation in a larger study, however, as it is based on only 42 disease-free survival events on ACT compared with 35 on ACTH.