How Low Should We Go? The Search for Balance in Management of Small Human Epidermal Growth Factor Receptor 2–Positive Breast Cancers

The articles that accompany this editorial feature work from two independent groups and provide important data for consideration by clinicians who treat small human epidermal growth factor receptor 2 (HER2) –positive breast cancers. Fehrenbacher et al present an analysis of outcomes among women with small, node-negative, HER2-positive tumors treated in the Kaiser Permanente Northern California system from 2000 to 2006, whereas Vaz-Luis et al present data from a similar cohort treated at National Comprehensive Cancer Network (NCCN) centers over a longer time period that spans the dissemination of trastuzumab into adjuvant breast cancer care. These data are of great interest to clinicians in the context of an ongoing struggle to define a threshold, if any exists, below which early-stage HER2-positive breast cancers have a sufficiently favorable prognosis to enable the withholding of trastuzumab-based cytotoxic combination therapy. Previous prognostic data in this subgroup have been scant and difficult to interpret. PREDICT (http://www.predict .nhs.uk/), the publicly available prognostic calculator from the United Kingdom that incorporates HER2 status, does not differentiate outcomes estimates below 1 cm, reflecting this paucity of data. The largest historical cohorts include one from MD Anderson that comprised 98 patients with T1a and T1b, node-negative, HER2-positive disease diagnosed between 1990 and 2002 and not treated with chemotherapy, in whom 5-year recurrence-free survival was 77% and distant recurrence–free survival (DRFS) was 86%. A similar cohort of 150 Italian patients diagnosed between 1999 and 2006, some of whom received chemotherapy, reported 5-year disease-free survival rates of 92% for patients with triple-positive disease and 91% for patients with hormone receptor–negative disease. Potential reasons for the differences in observed rates include inconsistencies in end point definition, increased use of endocrine therapy over time, and chemotherapy use in the Italian cohort, as well as a greater representation of patients with T1a disease in later cohorts, perhaps representing shifts in detection rates attributable to mammography screening. No patient in either the MD Anderson or the Italian cohort was treated with trastuzumab. Other data suggest that the incorporation of HER2-targeting with trastuzumab has shifted the survival curve even for low-risk, HER2positive tumors. Although most of the randomized trastuzumab plus chemotherapy trials excluded or dramatically underrepresented women with T1N0 tumors, the recently presented single-arm Adjuvant Paclitaxel/Trastuzumab (APT) trial of paclitaxel and trastuzumab included a large proportion of patients with T1N0 disease and demonstrated a 98% disease-free survival rate at 3 years, but did not include an untreated comparator arm. The debate regarding appropriateness of trastuzumab-based therapy in women with small HER2-positive tumors enters the cancer care context at a time of rising concern regarding overtreatment. In particular, the oncology community is increasingly aware of the precarious balance between the costs and effectiveness of expensive anticancer therapies in terms of both direct medical costs and the burden on patients, their families, and the health care system that serves them. Trastuzumab adds significantly to the cost of adjuvant breast cancer treatment. Our own analysis of a large commercial insurance database indicates a median cost of $3,187 per trastuzumab infusion, which translates to more than $57,000 for a year of adjuvant trastuzumab alone (S. Dusetzina, personal communication, March 2014) and does not include the additional costs of cytotoxic partner drugs, physician visits, travel expenses, and lost productivity, many of which come directly out of the pockets of patients. As oncologists, the impact of such costs on our patients compels us to consider this aspect of treatment decision making. In a recent survey by Zafar et al, 42% of patients with cancer describe significant or catastrophic burden from treatment costs, despite being insured. Leading national organizations, including the AmericanSocietyofClinicalOncology(ASCO),are increasingly focusing attention on value-based cancer care. ASCO’s recently formed Value in Cancer Care Task Force and ASCO’s annual Top Five List, which focuses on areas for practice improvement in cooperation with the American Board of Internal Medicine Foundation’s Choosing Wisely Campaign, areexamplesof increasingawareness thatchoosingthebest therapyforan individual patient involves careful consideration of the evidence base that supports that treatment’s benefit, as well as thoughtful evaluation of the burden the proposed treatment may impose on the patient in terms of cost, toxicity,andstrainonsocial,psychological,andemotionalresources. The debate regarding adjuvant trastuzumab-based treatment for small HER2-positive tumors crystallizes many of these concerns; this clinical scenario is in acute need of better evidence to inform patient care. The reports that accompany this editorial attempt to address two distinct and lingering questions in HER2-positive breast cancer: first, what is the natural history of small HER2-positive tumors; and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 20 JULY 1