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Predictive value of intratumoral signaling and immune infiltrate in primary breast cancer (PBC) for response to preoperative trastuzumab (T) vs trastuzumab + everolimus (T+E) in patients (pts) with early breast cancer (BC) : Unicancer RADHER trial results

Abstract : Background: Blockade of PI3K/AKT/mTOR pathway by E combined with T in HER2+ BC pts shows promising results. It has also been reported that T acted differently when used in PO setting with a lower implication of signaling blockade and a higher induction of ADCC when used alone in chemotherapy naive pts. Additionally, mTOR blockade has been experimentally reported to activate MAPK pathway through a feed-back loop effect. We present the results of a biological integrated approach including markers of PI3K/AKT/mTOR and MAPK pathways, proliferation and immune environment in HER-2 + PBC treated with T +/- E in PO setting. Methods: Eligible pts with HER2+ PBC (IHC 3+ or FISH/SISH+) amenable to surgery were randomized to receive T (loading dose 4 mg/kg, then 2 mg/kg/W), or T+E (10 mg/d) for a 6W PO treatment. All pts had baseline core needle biopsies, tissue collected at surgery and blood samples for biomarkers and pharmacokinetic analyses. FFPE samples were used for PIK3CA mutation status and IHC (pAKT, pS6K, eIF4E, LKB1, p4EBP1, Ki67, caspase 3, PTEN, CD8, CD68). Frozen samples were used for multiplex immunoanalyses of phosphorylated PI3K/AKT/mTOR and MAPKinase signaling proteins (p-AKT, p-GSK3, p-P70S6K, p-MEK1, p-ERK1/2, p-P90RSK). Results: FFPE and frozen tumor samples (n = 80), were obtained from 82 pts randomized from July 2008 to April 2012 (41 per arm). At baseline, only PIK3CA mutation status was predictive of clinical response, whatever the arm. No difference in the expression of phosphorylated signaling kinases was induced by exposure to T while T+E induced a significant activation of MAPKinase pathway. Between baseline and surgery we observed a down regulation of pAKT pS6K, LKB1, Ki67, a lower expression of PTEN and an increase in lymphocytes (CD8+) and macrophages (CD68+) infiltrates in both arms. Conclusions: These results confirm that in PO setting, T +/- E should mostly act via the activation immune response through tumor-associated lymphocytes and macrophages infiltrates. Rapid decrease in PTEN and LKB1 may be related to early cellular mechanism of resistance to HER2 inhibition. Clinical trial information: NCT00674414
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https://hal.archives-ouvertes.fr/hal-01320584
Contributor : Jean-Louis Merlin Connect in order to contact the contributor
Submitted on : Tuesday, May 24, 2016 - 10:33:39 AM
Last modification on : Monday, November 28, 2022 - 10:38:07 AM

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  • HAL Id : hal-01320584, version 1

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Mario Campone, Isabelle Treilleux, Julia Salleron, Monica Arnedos, Qing Wang, et al.. Predictive value of intratumoral signaling and immune infiltrate in primary breast cancer (PBC) for response to preoperative trastuzumab (T) vs trastuzumab + everolimus (T+E) in patients (pts) with early breast cancer (BC) : Unicancer RADHER trial results. ASCO 2016 annual meeting, Jun 2016, Chicago, IL, United States. pp.abstr 606. ⟨hal-01320584⟩

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