TRASTUZUMAB EFFECTIVE FOR T1b TUMORS

December 1, 2010 — The addition of trastuzumab (Herceptin) to chemotherapy is now the standard of care for many patients with early HER2-positive breast cancer, but not all; those will very small tumors are often not treated.

Women with small T1a (≤0.5 cm) and T1b (from 0.5 to 1 cm) node-negative (N0) cancers usually have an excellent prognosis and are not believed to derive a benefit from adjuvant therapy.

However, a review paper published in the December issue of the Lancet Oncology points out that there is "strong circumstantial evidence to justify some form of trastuzumab-based adjuvant therapy in most women with T1b, N0, HER2-positive breast cancers."

According to retrospective data, note authors Susana Banerjee, PhD, and Ian E. Smith, MD, from the Royal Marsden Hospital, London, United Kingdom, some small HER2-positive cancers might have a worse clinical outcome than others.

"Retrospective studies of . . . T1a,bN0 breast cancer, treated with local therapy and usually without adjuvant therapy, have consistently reported a 10-year relapse-free survival of more than 90%," the authors write. "However, many of these studies have limitations, including small sample size, short follow-up, and some patients receiving adjuvant systemic therapy."

The risk of recurrence in this subgroup of breast cancer patients and the true benefit of any adjuvant treatment remain unclear, they note. In addition, HER2-positive breast cancer, which accounts for approximately 15% to 20% of cases, is a distinct biologic subgroup and is associated with an aggressive clinical course.

Not Considered Low Risk

Drs. Smith and Banerjee note that retrospective data from several studies suggest that HER2 is a marker of poor prognosis in patients with small node-negative cancers. In fact, they point out, these tumors have a substantially increased risk for recurrence and should not be considered low risk.

As previously reported by Medscape Medical News, some researchers believe that all low-grade HER2-positive tumors should be treated with adjuvant systemic therapy, no matter what their size. Two studies that were presented at the 2008 San Antonio Breast Cancer Symposium (SABCS) found that patients with this tumor subtype have a poorer prognosis and a higher risk for recurrence.

"The biology of the tumor, and not the size or grade, matters most in these patients," Sian Tovey, MD, from the Glasgow Royal Infirmary, Scotland, who presented the results from one of the studies at the SABCS, told Medscape Medical News at the time. "Any patient who is HER2 positive should be categorized as high risk and should receive adjuvant trastuzumab therapy."

In their review, Drs. Smith and Banerjee point out that the number of women being diagnosed with T1a,bN0 primary tumors is rising because of improved breast cancer awareness and screening programs. Thus, there is a need for clarification of the optimal treatment.

Benefit Suggested, Inconsistent Guidelines

The pivotal adjuvant trastuzumab trials, which involved more than 14,000 patients, excluded women with tumors smaller than 1 cm. But there is indirect evidence that trastuzumab might benefit patients with these smaller tumors, they write. For example, a subset analysis of the Herceptin Adjuvant (HERA) trial showed that those with tumors 1 to 2 cm in size derived at least as much clinical benefit from 1 year of adjuvant trastuzumab as did the overall cohort (Lancet. 2007;369:29-36).

In another subanalysis from the Breast Cancer International Research Group 006 trial, results suggested that node-negative patients gained at least as much benefit from trastuzumab as did the overall group, both for disease-free and overall survival (SABCS 2006. Abstract 52). These results supported those from the HERA study, the authors note.

The lack of supportive evidence, however, places clinicians in a dilemma when they are trying to select appropriate therapy for this group of breast cancer patients. "Present guidelines for the systemic treatment of small, HER2-positive breast cancers are uncertain and inconsistent," Drs. Smith and Banerjee write.

Future Directions

Ideally, prospective randomized trials of trastuzumab-based treatment are needed for this population, but they are not likely to ever be conducted for a number of reasons, the authors write. Because of the low incidence of small HER2-positive breast cancers and the relatively low event rate, a large number of patients would be needed, which would be expensive. The design of trials has already proven difficult to agree upon, and successful recruitment to a randomized trial with a no-treatment group would be challenging. Finally, the choice of treatment for the investigational group is controversial.

Taking this into consideration, they suggest that the "next best approach would be a nonrandomized prospective study." Additional supportive evidence could be garnered from ongoing trials that include patients with small HER2-positive tumors.

The authors offer 2 more recommendations. One is to create prospective databases on the management of patients with HER2-positive cancers, which would provide retrospective analyses of outcomes associated with different treatments. The second is to incorporate molecular markers and multigene assays into clinical datasets, which might help identify and stratify relative risk within this subgroup.

"As in other areas of breast cancer management, this type of approach will eventually lead to a much more accurate prediction of which systemic therapies, if any, will most benefit each individual patient with these difficult, small, HER2-positive cancers," they conclude.

Dr. Smith reports receiving occasional honoraria for lecturing from Roche. Dr. Banerjee has disclosed no relevant financial relationships.

Lancet Oncol. 2010;11:1193-1199.