|LETTER TO EDITOR
|Year : 2020 | Volume
| Issue : 2 | Page : 399-400
Trastuzumab is not a one-man show: The sequence matters
National Oncology Centre, The Royal Hospital, Muscat, Sultanate of Oman
|Date of Submission||16-Mar-2020|
|Date of Decision||19-Mar-2020|
|Date of Acceptance||19-Mar-2020|
|Date of Web Publication||19-Jun-2020|
National Oncology Centre, The Royal Hospital, Muscat
Sultanate of Oman
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Venniyoor A. Trastuzumab is not a one-man show: The sequence matters. Cancer Res Stat Treat 2020;3:399-400
I read with interest the paper by Manuprasad et al. on their version of the short course (9-week) adjuvant trastuzumab for early breast cancer that delivered impressive results, along with the accompanying editorial. The 3-year disease-free survival (DFS) rate of 97.4% observed for their cohort of mostly T1, T2, and lymph node-negative (52%) patients is surprisingly close to the 98.7% DFS in the APT trial on small (<3 cm), node-negative, HER2-positive breast tumors by Tolaney et al. It is also worth mentioning that thanks to the high social index, the rural setting of Kerala is not necessarily applicable to the rest of India. The retrospective nature of the study and inevitable selection bias (no drop outs were reported by the authors) detracts from its value but it is still an interesting contribution to a controversial topic.
Conventionally, short course trastuzumab refers to a 6-month course as opposed to the standard of care of 1 year of trastuzumab. There are three published trials of the 6-month course, and the meta-analysis suggests that 1 year should remain the standard of care. This is acknowledged in most guidelines. However, the 1-year protocol leads to considerable financial toxicity, especially in resource constrained countries and hence the interest in even shorter courses.
The first trial using the 9-week course was the FinHer trial; this trial had a small subset of HER2-positive tumors (n = 232) with randomization to a 9-week course of (weekly) trastuzumab [Table 1]. Those receiving trastuzumab, not surprisingly, had a better event-free survival and overall survival (OS); the efficacy was maintained in the updated report. It was suggested  that future trialists trying to emulate the 9-week short course should stick to the same regimen, as it appeared that starting treatment upfront with trastuzumab, and using taxanes in higher doses seemed to be essential to its success.
The Finnish team replicated the trial in the larger (n = 2174) SOLD trial  using 3 doses of 3-weekly trastuzumab or 9 weekly doses, along with concurrent docetaxel. This trial was negative as it failed to prove noninferiority. However, the shorter subgroup that received docetaxel at 100 mg/m 2 had the same DFS as the 1-year trastuzumab group; the authors speculated that a higher dose of taxanes might be needed for altering the immune environment, increasing the effectiveness of trastuzumab.
Another noninferiority trial by an Italian group, the Short-HER trial  tested a combination of 3-weekly docetaxel along with 9 weekly doses of trastuzumab; this also fell short of the prespecified endpoint. These two trials were based on the presumption that first, a high dose of taxanes and second, administered upfront with trastuzumab, provides better benefit and may obviate the need for maintenance trastuzumab.
The E2198 study  randomized 227 women to a short course of the combination of of paclitaxel and trastuzumab delivered weekly for 12 cycles; this trial was powered to detect lower heart failure rates but outcomes, including heart failure rate, were similar. This is not surprising as, unlike anthracyclines, the cardiotoxicity of trastuzumab is not cumulative.
Meta-analysis  of the last 3 trials (SOLD, Short-HER and E2198) suggested a worse outcome for the shorter course, with increase in DFS events of 2.3% over a 6-year follow-up, with worse OS. However, cardiotoxicity was considerably lower.
In Manuprasad's study, weekly trastuzumab was given with weekly paclitaxel (or a combination of docetaxel/cyclophosphamide); the weekly dosing would lead to lower doses of taxanes at each schedule (though cumulative doses may be higher). The trastuzumab part was started after the initial non-trastuzumab containing regimen; thus both 'tenets' were ignored.
Trastuzumab has a long half-life (4 weeks) and a longer schedule (every 4-weekly) makes pharmacological sense, especially in the adjuvant setting where it targets small tumor cell clusters (and not tumor masses, as in the metastatic setting). It is rather surprising that the long half-life has not been exploited in most clinical trials.
A recent health economics study from India  suggested that only the 9-week course was cost effective; the regimens analyzed were based on the FinHer and Short-HER trials.
The natural history of HER2-positive breast cancer has changed with the introduction of trastuzumab, and the 1-year maintenance remains the standard of care. If there are financial limitations, some trastuzumab is definitely better than none, but this is not a one-man show; other drugs play important roles, and the best possible regimen must be used.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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