Letter to the Editor: Lapatinib Confounds Post-Hoc Weight Loss Analysis in the ALTTO Trial

Authors: Neil M. Iyengar MD1 and Jennifer A. Ligibel MD2
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  • 1 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; and
  • | 2 Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts

Re: Martel S, Lambertini M, Agbor-Tarh D, et al. Body mass index and weight change in patients with HER2-positive early breast cancer: exploratory analysis of the ALTTO BIG 2-06 trial. J Natl Compr Canc Netw 2021;19(2):181–189.

In the February 2021 issue of JNCCN, Martel et al1 reported an exploratory analysis of the ALTTO BIG 2-06 trial in which baseline body mass index ≥30 and weight loss ≥5.0% were associated with decreased survival in patients with HER2-positive breast cancer. The authors conclude that weight loss recommendations and trials should be approached cautiously.

These observations add to a growing literature demonstrating an association between obesity and increased risk of recurrence and mortality in HER2-positive breast cancer. In a recent meta-analysis, which included patients treated with trastuzumab, obesity was associated with worse disease-free and overall survival in HER2-positive breast cancer.2 This meta-analysis did not include information about weight change, but a prior report from the HERA trial did not show a relationship between weight change and survival in individuals treated with trastuzumab.3

So what is driving the relationship between weight loss and poor outcomes in this analysis of ALTTO? The toxicity profile of lapatinib presents a unique confounder. Specifically, 35% of patients in the ALTTO trial had grade 3/4 toxicity, 14.7% withdrew due to toxicity, and these rates were higher in obese participants. The rate of all-grade diarrhea was 75%, with 15% of patients experiencing ≥7 stools per day requiring hospitalization.4,5 Thus, weight loss in obese ALTTO participants may well be a surrogate indicator of ineffective treatment due to accentuated toxicity leading to treatment discontinuation. This theory is supported by 2 observations: (1) the association between weight loss and worse outcomes was primarily significant in the lapatinib-alone arm in ALTTO, and (2) weight loss was not associated with outcomes in trastuzumab-treated patients in HERA. Information from ALTTO regarding the relationships among weight loss, toxicity, and treatment discontinuation would be helpful in assessing this source of potential confounding.

The presence of undiagnosed metastatic disease or other comorbid conditions can also confound analyses of weight change and cancer outcomes. In this analysis of ALTTO, the authors acknowledge that they were unable to discern purposeful versus involuntary weight loss. Prospective randomized control trials are needed to overcome these multiple sources of unavoidable confounding.

Should weight loss be approached cautiously in patients with HER2-positive breast cancer as the authors suggest? Given the above considerations, and that lapatinib is not part of standard adjuvant treatment, we would not use these post hoc observational analyses for the basis of clinical recommendations.

References

  • 1.

    Martel S, Lambertini M, Agbor-Tarh D, et al. Body mass index and weight change in patients with HER2-positive early breast cancer: exploratory analysis of the ALTTO BIG 2-06 trial. J Natl Compr Canc Netw 2021;19:181189.

    • Crossref
    • PubMed
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  • 2.

    Lohmann AE, Soldera SV, Pimentel I, et al. Association of obesity with breast cancer outcome in relation to cancer subtypes: a meta-analysis. J Natl Cancer Inst 2021;djab023.

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  • 3.

    Yerushalmi R, Dong B, Chapman JW, et al. Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials. Ann Oncol 2017;28:15601568.

  • 4.

    Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol 2016;34:10341042.

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    • Search Google Scholar
    • Export Citation
  • 5.

    Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone, trastuzumab alone, their sequence, or their combination in the adjuvant treatment of HER2-positive early breast cancer [abstract]. J Clin Oncol 2014;32(Suppl):Abstract LBA4.

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    • Export Citation
  • 1.

    Martel S, Lambertini M, Agbor-Tarh D, et al. Body mass index and weight change in patients with HER2-positive early breast cancer: exploratory analysis of the ALTTO BIG 2-06 trial. J Natl Compr Canc Netw 2021;19:181189.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Lohmann AE, Soldera SV, Pimentel I, et al. Association of obesity with breast cancer outcome in relation to cancer subtypes: a meta-analysis. J Natl Cancer Inst 2021;djab023.

    • Search Google Scholar
    • Export Citation
  • 3.

    Yerushalmi R, Dong B, Chapman JW, et al. Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials. Ann Oncol 2017;28:15601568.

  • 4.

    Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol 2016;34:10341042.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone, trastuzumab alone, their sequence, or their combination in the adjuvant treatment of HER2-positive early breast cancer [abstract]. J Clin Oncol 2014;32(Suppl):Abstract LBA4.

    • Search Google Scholar
    • Export Citation
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