Abstract OT3-2-06: NEOPAL: A randomized phase II study comparing RCB response to neoadjuvant chemotherapy or letrozole-palbociclib in PAM50 defined postmenopausal luminal breast cancer
Authors: Cottu Paul H , Duhoux François , Lemonnier Jérôme , Bonnefoi Hervé , Vincent Salomon Anne , Asselain Bernard , Delaloge Suzette 
Published: May 2015

Abstract
Background: HR-positive BC heterogeneously sensitive to neoadjuvant chemotherapy (NEC), with pCR rates varying from 2 to 20% at most. The alternative systemic primary therapy in ER+ breast cancer is neoadjuvant endocrine therapy (NET). Clinical response with NET is roughly 50%. It has also been suggested that NET may yield a higher rate of breast conserving surgery than NEC in ER+ disease, although pCR remains under 10% in both instances. No definite pathological criteria for response to NET has been defined so far. Within this context, the PAM 50 signature has been evaluated on numerous series of pts and has been shown to highly correlate with Residual Cancer Burden (RCB – Symmans, JCO 2007) and pCR in patients treated with NEC, as well as with the PEPI score in patients treated with NET (Ellis 2011). Palbociclib + Letrozole has been shown as a very active association as first-line metastastic treatment of HR+ Her2- BC pts on both response rates and progression free survival (Paloma-1 study). This combination could represent an interesting alternative to CT in carefully selected Luminal BC pts.
Trial design and statistical methods: Open-label, randomized, parallel, multicenter, exploratory phase II study, comparing sequential standard NEC (3 FEC 100 followed by 3 Docetaxel 100) and a same duration letrozole + palbociclib combination as neoadjuvant treatment of stage II-IIIA PAM 50 defined Luminal A-Node+/Luminal B breast cancer. Medical treatment will be followed by adequate surgery and complementary chemotherapy and radiation therapy as clinically indicated. All pts will receive adjuvant chemotherapy. Randomizations are equally balanced between the 2 arms and stratified based on T2 versus T3-T4 and PAM 50 luminal A vs luminal B. A Fleming 2-step statistical design will be used in the experimental arm with an intermediate futility analysis. The target accrual is 60 pts evaluable for RCB in both arms.
Eligibility criteria: Newly diagnosed pts with ER+, Her2-negative, stage II-III breast cancer will be tested for PAM50 signature. Only luminal A N+ or Luminal B (PAM50 ROR (Prosigna™) centralized evaluation) pts will be eligible and randomized. Pts must be post-menopausal women, aged &gt; 18 years, bear operable unilateral invasive BC, and not be candidate or uncertain for breast conservation.
Specific aims: The main objective of this trial is to evaluate the ability of each treatment strategy to provide RCB 0-I at surgery. Secondary end-points are: Clinical/radiological response rates in each treatment arm (RECIST 1.1), safety (CTC-AE V4.0), relative dose intensity of each drug in both arms, positive and negative predictive values of PAM50 ROR-defined status, assessment of several biomarkers as potential predictors of clinical and pathological response, rates of BCS, with regard to the initially planned surgery, all in both arms
Target accrual: This study has started in autumn 2014. 132 pts will have to be included (estimation of 10% risk of non evaluable pts). As about 10% of PAM50 evaluable pts will be classified as non luminal, and taking into account potential technical failures, about 180 pts will be screened.
Citation Format: Paul H Cottu, François Duhoux, Jérôme Lemonnier, Hervé Bonnefoi, Anne Vincent Salomon, Bernard Asselain, Suzette Delaloge. NEOPAL: A randomized phase II study comparing RCB response to neoadjuvant chemotherapy or letrozole-palbociclib in PAM50 defined postmenopausal luminal breast cancer [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 OT3-2-06.