Abstract ES2-2: Neoadjuvant therapy in HER2 positive breast cancer, latest developments and biomarkers and how it serves as a discovery platform
Authors: Loibl Sibylle 
Published: May 2015

Abstract
The treatment of HER2+ early breast cancer has been revolutionized by inducing a specific antibody targeting the HER2+ protein. This has changed the prognosis of the HER2+ breast cancer patients from being a group with a very bad prognosis to a group with a very good prognosis. New concepts such as using a double anti-HER2 treatment with either two antibodies or an antibody and a tyrosine kinase inhibitor have been developed.
The neoadjuvant therapy with trastuzumab and pertuzumab in addition to a taxane over 12 weeks increased the pCR (pathological complete response) rate from 29% to 46%. The combination of trastuzumab with lapatinib in addition to paclitaxel was investigated in several neoadjuvant trials and showed an increase in pCR rate as well. However the adjuvant ALTTO study failed to show a statistically significant improvement in disease-free survival by adding lapatinib as did the much smaller and not for the survival powered Neo-ALtto study. Results from the APHINITY study investigating the double antibody treatment are not yet available. Reaching a pCR is crucial for the HER2+ breast cancer patients, especially in the group of HR- disease as an increase in pCR translating to an improved survival.
A very interesting concept is the use of a chemo-free treatment with just the dual anti-HER2 treatments +/- an endocrine agent. The Neosphere study using on the dual antibody treatment reached a pCR rate of 16.8% (5.9% in HR+ and 27.3% in HR-). The TBCR006 study used a dual anti-HER2 treatment of lapatinib and trastuzumab, and patients with a HR+ breast cancer received letrozole (+GnRH in premenopausal women). This resulted in a pCR rate of 22% (18% in HR+ and 28% in HR-).
In all neoadjuvant studies the group of patients with hormone-receptor positive disease derived a much smaller benefit from the dual anti-HER2 treatment. Still we consider the treatment to be used irrespective of the hormone-receptor status. The assessment of the PI3KCA mutation status of the tumor has been investigated recently. The results across different studies are very homogeneous. Overall the patients whose tumor harbor a PIK3CA mutation show significantly lower pCR rates with a double blockade than the wt tumors, irrespective of the accompanying treatment. The differences with a single anti-HER2 agent are smaller but show in the same direction. PIK3CA genotype as well as the hormone receptor status have proven to be independent predictive factors for pCR with a double anti-HER2 treatment.
Although the numbers are small and the p-value not significant the FinHER data suggest a benefit from trastuzumab confined to the PIK3CA mutant cohort. The PI3K pathway seems to play a role in HER2 resistance but not exclusively and new markers are currently under investigation. Breast cancers with a high rate of tumour infiltrating lymphocyctes (TILs) and up as well as down regulating immune markers show a better response to chemotherapy (+/- anti-HER2 treatment).
To investigate new markers and treatments a better selection of the patients based on response is needed. The implementation of a window of opportunity either as a stand-alone study or an inbuilt phase of larger study is a chance to better investigate new drugs and select new biomarkers.
Citation Format: Sibylle Loibl. Neoadjuvant therapy in HER2 positive breast cancer, latest developments and biomarkers and how it serves as a discovery platform [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES2-2.