Purpose: Determine long term survival benefits and the balance of risk and benefit of adjuvant Herceptin (Trastuzumab) in HER2 positive breast cancer.

Methods: Early results from three large randomized trials showed that adjuvant Herceptin results in significant cancer recurrence reduction in high risk HER2 positive breast cancers but is also associated with cardiac toxicity. We constructed a Markov state transition decision analytic model to evaluate these tradeoffs and predict long term survival benefits. We explored prototypic scenarios that varied in age, risk of recurrence, and cardiac toxicity rates. One-way sensitivity analyses were done for age; hazard ratio for Herceptin efficacy; recurrence risk and cardiac toxicity. Our base case was a 50 year-old, 2 cm, node positive, ER/PR negative patient with a 6% cumulative risk of cardiac toxicity.

Results: Survival rates and the cardiac death rates for the base case and hypothetical cases with moderate and low risk of cancer recurrence are illustrated in the table below. In patients with high risk of cancer recurrence Herceptin provides impressive long term survival benefits. However, Herceptin provides only modest benefit in patients with average risk of cancer recurrence and no additional benefit in the elderly patients with low risk of cancer recurrence.

 Conclusions: The addition of Herceptin in HER2 positive cancer is more effective than standard chemotherapy alone in patients with high and moderate risk of cancer recurrence. However, the incremental benefit decreases with advancing age, higher risk of cardiac toxicity and in patients with lower risk of recurrence. This is a useful clinical tool to quantify risks and benefits of adjuvant Herceptin and in predicting long term survival in HER2 positive patients.

Projected Survival Benefits with Adjuvant Herceptin

Case Scenarios	Treatment Strategy	Cumulative Cardiac Toxicity (%)	QALYs	10 Year DFS (%)	10 Year Cancer Deaths (%)	10 Year Cardiac Deaths (%)
50 Yr 2 Cm, L. Node +  ER/PR –  EF 60%	Chemotherapy (CT)	0.8	22.4	71.1	17.2	0.06
	CT and Herceptin	6	26.6	81.7	8.5	0.7
50 Yr: 2cm L. Node – ER/PR + EF 60%	CT and hormonal (CTH)	0.8	29.4	88.3	3.8	0.06
	CTH and Herceptin	6	30.5	90.7	1.7	0.7
70 Yr 2 Cm, Node –  ER/PR+ EF 50%	CTH	0.8	15.3	70	1.6	0.06
	CTH and Herceptin	19	15.0	68.9	0.8	2.0