Trastuzumab (Herceptin) has revolutionised the care of HER2-positive (HER2+) early breast cancer and is the standard treatment for tumours larger than 1cm. By contrast, most small (≤ 1cm) breast cancers have a favourable prognosis and are widely believed not to benefit from adjuvant treatment (treatment given in addition to primary therapy). But according to a review of the evidence published in the December issue of The Lancet Oncology, there is strong circumstantial evidence to suggest that most women with these small cancers could benefit from, and should be offered, adjuvant trastuzumab (the most commonly prescribed anti-HER2 drug).

Improved breast awareness and the introduction of mammography screening have resulted in a steady increase in the number of women being diagnosed with small, node-negative HER2+ cancers.

“T1a,bN0 [small, node-negative] breast cancer, treated with local therapy and usually without adjuvant therapy, have consistently reported a 10-year relapse-free survival (RFS) of more than 90%. However, many of these studies have limitations, including small sample size, short follow-up, and some patients receiving adjuvant systemic therapy”, explain Ian Smith and Susana Banerjee from the Royal Marsden Hospital, London, UK.

As a result, they say, the risk of recurrence of these small cancers is unclear, and the true benefit of any adjuvant treatment is not known.

Indeed, they add, retrospective data from several studies suggest that HER2 is a marker of poor prognosis in patients with small node-negative cancers, and in fact, these small tumours have a substantially increased risk of recurrence and should not be considered low risk.

The landmark trials establishing the efficacy of adjuvant trastuzumab did not include patients with tumours smaller than 1cm because they were believed to have an excellent prognosis. But this lack of randomised trial data has given clinicians a dilemma: “What is the real prognosis for small HER2-positive breast cancers and does the potential reduction in recurrence warrant the toxic effects and potential risks, including, in particular, neutropenic sepsis and cardiac dysfunction?”

According to the authors, some indirect evidence from key trials suggests that tumours smaller than 1cm might benefit significantly from trastuzumab treatment. For example, a subset analysis of the Herceptin Adjuvant (HERA) trial showed that patients with tumours of 1–2cm gained at least as much clinical benefit from 1 year of adjuvant trastuzumab as the overall group. Additionally, a subgroup analysis of the Breast Cancer International Research group-006 trial, reported that node-negative patients derived at least as much benefit (disease free survival and overall survival) from trastuzumab as the overall cohort.

The authors point out that because of the lack of supportive evidence, current guidelines for the adjuvant treatment of these small cancers are uncertain, and this is reflected in inconsistent and divided clinical practice.

To resolve this uncertainty, randomised trials of trastuzumab-based treatment for small HER2+ cancers are needed. But this, they claim, is unlikely to be done because of problems establishing such trials including: recruiting a no-treatment group in light of retrospective evidence favouring trastuzumab therapy; and the need for a large international trial and associated funding problems. They add: “Taking this into consideration the next best approach would be a non-randomised prospective study.”

The article discusses two further recommendations—the creation of prospective databases on the management of patients with HER2+ cancers that should provide further indirect evidence of the benefits associated with different treatments; and the inclusion of molecular markers and multigene tests in clinical datasets to make a more accurate prediction of which treatments will benefit each individual patient.

Smith and Banerjee conclude: “We believe that there is now strong circumstantial evidence to justify some form of trastuzumab-based adjuvant therapy in most women with T1b (>0.5—≤1cm), N0, HER2-positive breast cancers...We recommend that the benefits and risks of adjuvant trastuzumab should be discussed with patients.”


Source: Lancet Oncology