Is adjuvant trastuzumab cost-effective for HER2-positive T1bN0 breast cancer?

An economic model to estimate the cumulative costs and QALYs gained with adjuvant trastuzumab in hypothetical cohorts of women with T1bN0 breast cancer

A number of randomised clinical trials have reported improved disease-free and overall survival when trastuzumab is administered concurrent with or after adjuvant chemotherapy in HER2-positive breast cancer, and recent economic evaluations have also suggested acceptable value for money. However, these observations have been noted primarily in patient cohorts with moderate to high baseline risks of disease recurrence, as inclusion criteria for the pivotal adjuvant trastuzumab trials have generally specified node-positive or node-negative disease with tumours of >1.0 cm (≥T1cN0). The role of adjuvant trastuzumab is less clear in light of the variable 10-year baseline relapse risk (10%–30%) reported for patients with small (≤1 cm), node-negative tumours. Trastuzumab is not currently approved for T1bN0 tumours in most countries, although updated National Comprehensive Cancer Network (NCCN) guidelines have recommended considering adjuvant trastuzumab for node-negative tumours measuring 0.5–1.0 cm (T1bN0) given their potentially aggressive biology and uncertain relapse risk.

In light of this clinical uncertainty and the high acquisition costs of trastuzumab, a group of researchers led by Mr C. Skedgel of the Atlantic Clinical Cancer Research Unit, Centre for Clinical Research, Halifax, Canada examined the ‘value for money’ associated with adjuvant trastuzumab in women with T1bN0 breast cancer in terms of the likelihood of such a strategy meeting a $100 000 per quality-adjusted life year (QALY) gained cost-effectiveness threshold over a plausible range of baseline recurrence risks.

They developed an economic model to estimate the cumulative costs and QALYs gained with adjuvant trastuzumab, administered concurrent with or sequential to adjuvant chemotherapy in hypothetical cohorts of women with T1bN0 breast cancer following curative-intent surgical excision of their tumour. The cohorts were distinguished by age at entry into the model and included ages 40, 50, 60 and 70. The model took a state-transition approach and modelled the probability of moving among different health states within a 1-month period or cycle. The costs and QALYs associated with each health state, weighted by the proportion of the cohort in each state in each cycle, were aggregated up to age 100 to represent a lifetime horizon and discounted at 3% annually.

The primary analysis took an incremental approach, comparing trastuzumab plus chemotherapy with chemotherapy alone. A secondary analysis took an ‘all-or-nothing’ approach, comparing trastuzumab plus chemotherapy with neither treatment.

The primary analysis suggested that concurrent trastuzumab plus adjuvant chemotherapy was likely to meet the $100 000 threshold at recurrence risks of 29–35%. Sequential trastuzumab was less likely to meet such a threshold. The secondary analysis was more favourable for both trastuzumab strategies, but of limited relevance as clinical benefits were predominantly driven by chemotherapy without trastuzumab.

Although the expected costs of adjuvant therapy were very similar across the age cohorts, patients in the younger cohorts had greater lifetime QALY gains than patients in the older cohorts and were therefore likely to meet a $100 000 threshold at lower baseline recurrence rates.

The secondary ‘all-or-nothing’ analysis, comparing trastuzumab and chemotherapy with no adjuvant chemotherapy strategy, was much more favourable for both concurrent and sequential trastuzumab strategies, but would only be relevant if chemotherapy would not be considered in clinical practice without adjuvant trastuzumab for women with HER2-positive breast cancers. Adjuvant chemotherapy, though, was the comparator arm in clinical trials of adjuvant trastuzumab plus chemotherapy for HER2-positive breast cancers with tumours of >1 cm (≥ T1c tumours). Moreover, the QALY gains associated with adjuvant systemic therapy were predominantly driven by chemotherapy without trastuzumab over the entire recurrence range tested. Although no adjuvant chemotherapy may be a reasonably clinical strategy in smaller HER2-positive breast cancers, there is little indication that it is an appropriate ‘economic’ comparator when seeking to consider the incremental cost and benefit of concurrent or sequential trastuzumab.

The aggregate cost of adjuvant systemic therapy, with or without adjuvant trastuzumab, decreased as the baseline risk of recurrence increased, suggesting that the upfront costs of adjuvant therapy may be offset to some degree by relative savings associated with the number of recurrences avoided. Despite these declining costs, and the increasing proportion of incremental QALYs associated with adjuvant trastuzumab as baseline risk increased, trastuzumab was consistently associated with a disproportionate share of the costs of adjuvant therapy relative to incremental QALY gains, particularly at lower recurrence rates. Note, though, that the analysis only considered direct costs to payers, including indirect societal costs would most likely increase the net savings from recurrences avoided, and therefore, improve the relative cost-effectiveness of adjuvant therapy.

As in all economic evaluations, the authors warned that their results may not be generalizable to all health care jurisdictions given the potential for substantial differences in costs and/or clinical practice compared with the Canadian health care system. As well, other jurisdictions may have different requirements for reimbursement, which may or may not include the explicit evaluation of value for money. They were also forced to rely on a number of assumptions due to sparse clinical data around T1bN0 cancers, including estimates of baseline relapse risks without systemic therapy. The observed favourability of concurrent over sequential trastuzumab was based on an indirect across-trials comparison that incorporated estimates of treatment benefit from multiple studies, although this was concordant with preliminary results from the one randomized clinical trial that directly examined concurrent versus sequential trastuzumab. However, their probabilistic analysis over a range of baseline relapse risks allowed for variability around input parameters, including the underlying baseline recurrence risk, the relative risk reduction associated with concurrent and sequential trastuzumab and the duration of trastuzumab benefit.

The authors concluded that their analysis shows that concurrent trastuzumab plus adjuvant chemotherapy appears to offer a favourable value for money at the upper ranges of baseline recurrence risks reported to date, particularly in younger patients, although more precise estimates of underlying risk are required to confirm the cost-effectiveness of adjuvant trastuzumab in T1bN0 breast cancer.

This work was supported by the Beatrice Hunter Cancer Research Institute, with funding from the Breast Cancer Society of Canada and the Queen Elizabeth II Foundation Award for breast cancer research. Grant number at CDHA for finances. Account 1010777 SAP 691883.