SABCS 2011 Report – New standards in the management of HER2+ breast cancer tumours

by Dr Sunil Upadhyay – The San Antonio Breast Cancer Symposium 2011 was as exciting as ever with much new data and up-dates presented. Despite the ‘hot off the press’ news and animated debates on the rising cost of cancer care, timely in a global recession, the announcement of two trial results attracted the largest audiences and longest discussion times, CLEOPATRA and BOLERO 2.

Data from CLEOPATRA, a Phase III, randomised, double blind, placebo-controlled registration trial to evaluate the efficacy and safety of placebo + trastuzumab + docetaxel versus pertuzumab + trastuzumab + docetaxel in patients with previously untreated HER2-positive metastatic breast cancer, were presented by Jose Baselga, from the Massachusetts General Hospital, and simultaneously presented and published in the New England Journal of Medicine January 12, 2012 issue.

Pertuzumab is the first in a new class of targeted anticancer agents known as HER2 dimerisation inhibitors and is designed to prevent the pairing of HER2 with other HER receptors. By inhibiting the dimerisation of the HER family of receptors, pertuzumab and trastuzumab block cell signalling, leading to inhibition of cell growth and ultimately cancer cell death. Pertuzumab and trastuzumab, both bind to the HER2 receptor although to different parts and hence compliment each other in their action. Although the drug has been around for many years, the best use of pertuzumab, alone or in combination, remains unknown. It may have an effect on the PIK3 kinase pathway. The CLEOPATRA trial was designed to look for PFS and overall survival in HER2-positive metastatic breast cancer patients who relapsed following prior systemic therapies including trastuzumab and/or a taxane.

The patients were randomised to receive docetaxel with trastuzumab alone (n=406) or docetaxel with trastuzumab plus pertuzumab (n=402). The results presented by Jose Baselga showed marked prolongation of median PFS with addition of pertuzumab.

CLEOPATRA: Efficacy endpoints

	Docetaxel + trastuzumab + pertuzumab	Docetaxel + trastuzumab +placebo	HR	p-value
Median PFS	18.5 months	12.4 months	0.62	<0.001
Interim OS	Not reported	Not reported	0.64	0.005
Objective response rate	80.2%	69.3%	–	0.001

Baselga J et al. Abstract S 5-5; SABCS 2011

The commonly seen PFS of 12.4 months in these types of patients was dramatically increased by 50% to 18.5 months with addition of pertuzumab in this study. The interim analysis of overall survival showed a strong trend in favour of the pertuzumab group of patients. The safety profile was essentially identical including left ventricular dysfunction between the two arms.

However, it is essential to note that only about 10% of the HER2-positive patients received trastuzumab in the adjuvant setting, which is unexpected in the western world population in this day and age. Similarly, only 50% received prior chemotherapy. Therefore, it is difficult to imagine how these data are going to provide strong support for the use of pertuzumab with trastuzumab and docetaxel (three drugs together) in the European population. However, future updated results may show significantly improved overall survival gains with this three-drug combination. The preliminary results from NeoSphere trial in the neo-adjuvant setting did indicate superior activity from this approach.

Currently various trials are in progress on the role of adjuvant pertuzumab and trastuzumab in the management of HER2-positive breast cancer. APHINITY trial under the umbrella of the Breast International Group is already underway and Von Minckwitz presented the design of this trial as a poster at SABCS 2011 (Abs 0T1-02-04).