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Table of Contents
LETTER TO EDITOR
Year : 2020  |  Volume : 3  |  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 Submission16-Mar-2020
Date of Decision19-Mar-2020
Date of Acceptance19-Mar-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Ajit Venniyoor
National Oncology Centre, The Royal Hospital, Muscat
Sultanate of Oman
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_86_20

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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

How to cite this URL:
Venniyoor A. Trastuzumab is not a one-man show: The sequence matters. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Sep 19];3:399-400. Available from: http://www.crstonline.com/text.asp?2020/3/2/399/287277



I read with interest the paper by Manuprasad et al.[1] on their version of the short course (9-week) adjuvant trastuzumab for early breast cancer that delivered impressive results, along with the accompanying editorial.[2] 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.[3] 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.[4] 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;[5] 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.[6] It was suggested [7] 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.
Table 1: The shorter course regimens: Sequencing

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The Finnish team replicated the trial in the larger (n = 2174) SOLD trial [8] 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 [9] 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 [10] 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 [4] 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,[1] 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).[11] It is rather surprising that the long half-life has not been exploited in most clinical trials.

A recent health economics study from India [12] 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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Manuprasad A, Shenoy PK, Jones J, Vinin NV, Dharmarajan A, Muttath G. Short-course adjuvant trastuzumab in breast cancer: Experience from a tertiary cancer center in rural India. Cancer Res Stat Treat 2020;3:69-73.  Back to cited text no. 1
  [Full text]  
2.
Akram Hussain SM. Molecular-based screening and therapeutics of breast and ovarian cancer in low- and middle-income countries. Cancer Res Stat Treat 2020;3:81-4.  Back to cited text no. 2
  [Full text]  
3.
Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 2015;372:134-41.  Back to cited text no. 3
    
4.
Goldvaser H, Korzets Y, Shepshelovich D, Yerushalmi R, Sarfaty M, Ribnikar D, et al. Deescalating adjuvant trastuzumab in HER2-positive early-stage breast cancer: A systemic review and meta-analysis. JNCI Cancer Spectr 2019;3:pkz033.  Back to cited text no. 4
    
5.
Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809-20.  Back to cited text no. 5
    
6.
Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: Final results of the FinHer Trial. J Clin Oncol 2009;27:5685-92.  Back to cited text no. 6
    
7.
Venniyoor A. Shorter course of trastuzumab: Caveat emptor. Indian J Med Paediatr Oncol 2011;32:55-6.  Back to cited text no. 7
[PUBMED]  [Full text]  
8.
Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, et al. Effect of adjuvant trastuzumab for a duration of 9 weeks vs. 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: The SOLD randomized clinical trial JAMA Oncol 2018;4:1199-206.  Back to cited text no. 8
    
9.
Conte P, Frassoldati A, Bisagni G, Brandes AA, Donadio M, Garrone O, et al. Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: Final results of the phase III randomized short-HER study‡. Ann Oncol 2018;29:2328-33.  Back to cited text no. 9
    
10.
Schneider BP, O'Neill A, Shen F, Sledge GW, Thor AD, Kahanic SP, et al. Pilot trial of paclitaxel-trastuzumab adjuvant therapy for early stage breast cancer: A trial of the ECOG-ACRIN cancer research group (E2198). Br J Cancer 2015;113:1651-7.  Back to cited text no. 10
    
11.
Levêque D, Gigou L, Bergerat JP. Clinical pharmacology of trastuzumab. Curr Clin Pharmacol 2008;3:51-5.  Back to cited text no. 11
    
12.
Gupta N, Verma RK, Gupta S, Prinja S. Cost effectiveness of trastuzumab for management of breast cancer in India. JCO Glob Oncol 2020;6:205-16.  Back to cited text no. 12
    



 
 
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  [Table 1]


This article has been cited by
1 Authorsę reply to Agarwal et al. and Venniyoor
Avaronnan Manuprasad,PraveenKumar Shenoy,Joneetha Jones,NV Vinin,Adarsh Dharmaraj,Geetha Muttath
Cancer Research, Statistics, and Treatment. 2020; 3(2): 402
[Pubmed] | [DOI]



 

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