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Skip Chemo for Older Patients With HER2+ Breast Cancer?

— Less than one-month survival loss at 3 years with trastuzumab monotherapy

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The vial and packaging of Herceptin (trastuzumab)

Adjuvant trastuzumab (Herceptin) failed to demonstrate noninferiority versus trastuzumab plus chemotherapy for older patients with early HER2-positive breast cancer, but trastuzumab alone still warrants consideration for selected patients, investigators in a randomized trial concluded.

Single-agent trastuzumab resulted in a 3-year disease-free survival (DFS) of 89.5% versus 93.8% with the addition of chemotherapy. The difference represented a 36% increase in the hazard for death or progression with the monotherapy; that came with a confidence interval exceeding the upper limit of 1.69 for the hazard ratio, prespecified as the noninferiority threshold for trastuzumab monotherapy.

But the estimated loss of survival at 3 years without chemotherapy was less 1 month, and trastuzumab monotherapy was better tolerated, Masataka Sawaki, MD, PhD, of Aichi Cancer Center Hospital in Nagoya, Japan, and coauthors reported in the .

"In light of the lower toxicity and more favorable HRQoL (health-related quality of life) profile, trastuzumab monotherapy can be considered an adjuvant therapy option for selected older patients," the authors concluded.

The HRQoL assessment was an important addition to the evaluation of adverse events, because chemotherapy is associated with significant deterioration of HRQoL, they continued. "Consequently, HRQoL deterioration, even if temporary, is important when deciding whether to receive chemotherapy."

Biomarker studies are required to provide "a more definitive answer to anti-HER2 therapy without chemotherapy."

Agreeing with the conclusions of Sawaki and colleagues, authors of an stated that the " provide convincing evidence that clinicians are good at identifying patients who are at low risk of recurrence even without receiving chemotherapy." Other studies have clearly shown that chemotherapy is not necessary to achieve a pathologic complete response in the neoadjuvant setting and that molecular subtyping can help identify such "exceptional responders."

Future studies should take these lessons into account to integrate molecular subtyping to achieve more focused treatment de-escalation, concluded Evandro de Azambuja, MD, PhD, of Institut Jules Bordet in Brussels, and coauthors.

"On the basis of the [Japanese] trial, it is possible to consider that adjuvant trastuzumab monotherapy could be an option for a subset of patients, particularly those who may have a higher risk of toxicity with chemotherapy and those with a lower anatomic risk of disease recurrence," the editorialists wrote.

"It is important to stress, however, that the choice of therapy in older patients should never be made on the basis of age alone. Comprehensive geriatric assessment is the standard of care for evaluation before chemotherapy and should generate a care plan to be implemented during treatment to minimize the risk of complications and maintain QoL and functionality."

Although adjuvant trastuzumab monotherapy avoids toxicity associated with chemotherapy, the agent is not used by itself in clinical practice because its benefit has not been investigated, Sawaki and coauthors noted. To address the issue, investigators at 99 Japanese centers enrolled patients ages 70 to 80 with early HER2-positive breast cancer, treated with curative surgery. The patients were randomized to trastuzumab alone or with physician's choice among seven standard-of-care chemotherapy regimens.

The primary endpoint was DFS, comparing treatment arms by HR. Investigators calculated restricted mean survival time (RMST) for each arm as a supplementary analysis. Secondary endpoints included OS, relapse-free survival (RFS), adverse events (AEs), and HRQoL. The threshold HR of 1.69 for noninferiority was developed from a physician questionnaire aimed at establishing a clinically meaningful advantage.

Data analysis included 266 patients, median age of 73.5, with median follow-up of 4.1 years. Most patients had stage I (43.6%) or stage IIa (41.7%) disease, followed by 13.5% with stage IIb and 1.1% with IIIa.

A planned analysis showed a 4.3 percentage-point difference in DFS, representing a hazard ratio of 1.36 for the comparison of trastuzumab monotherapy versus trastuzumab plus chemotherapy. The 95% confidence interval was 0.72 to 2.58, far exceeding the 1.69 upper bound for noninferiority stipulated in the trial design. The difference in RMST for DFS between the two treatment arms was -0.39 months (95% CI -1.71 to 0.93).

The 3-year RFS was 92.4% with trastuzumab alone and 95.3% with trastuzumab plus chemotherapy (HR 1.33, 95% CI 0.63-2.79). The RMST difference at 3 years was -0.41 months (95% CI -1.51 to 0.68). The 3-year OS was 97.2% vs 96.6% (HR 1.07, 95% CI 0.36-3.19), and distant DFS at 3 years was 93.1% with trastuzumab alone and 96.8% with chemotherapy (HR 1.42, 95% CI 0.64-3.17). Breast cancer-specific survival at 3 years was 99.2% in each arm.

The chemotherapy arm had a 70.6% incidence of grade 3/4 AEs, and almost all AEs (all grades) occurred significantly more often in the chemotherapy arm. HRQoL deterioration rates were significantly higher in the chemotherapy group at 2 months (48% vs 31%, P=0.016) and at 1 year (38% vs 19%, P=0.009).

  • author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined 鶹ý in 2007.

Disclosures

The study was supported by the Public Health Research Foundation of Japan.

Sawaki reported having no relevant relationships with industry. One or more coauthors reported relationships with Chugai, Teijin Pharma, Pfizer, Ono, Zeria, Daiichi Sankyo, Kyowa Hakko Kirin, Eisai, AstraZeneca, Novartis, Eli Lilly, Nippon Kayaku, Taiho, Asahi Kasei, Shionogi, Genomic Health, Takeda, MSD Oncology, Maruho, Bayer, Statcom, Sanofi, Medical Member System, and Taiho.

De Azambuja disclosed relationships with Genentech, SeaGen, Novartis, Zodiac, AstraZeneca, Servier, Pfizer, and GlaxoSmithKline.

Primary Source

Journal of Clinical Oncology

Sawaki M, et al "Randomized controlled trial of trastuzumab with or without chemotherapy for HER2-positive early breast cancer in older patients" J Clin Oncol 2020; DOI: 10.1200/JCO.20.00184.

Secondary Source

Journal of Clinical Oncology

De Azambuja E, et al "Are we RESPECTing older patients with breast cancer?" J Clin Oncol 2020; DOI: 10.1200/JCO.20.02329.