Abstract PD17-06: Immunohistochemical markers and determinants of clinical response in the Penelope-B trial

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-03, Vol.83 (5_Supplement), p.PD17-06-PD17-06
• Main Authors: Knudsen, Erik S., Rachakonda, Sivaramakrishna, Marmé, Frederik, Martín, Miguel, Untch, Michael, Bonnefoi, Hervé R., Schmitt, Wolfgang D., Kim, Sung-Bae, Bear, Harry D., Witkiewicz, Agnieszka, Im, Seock-Ah, DeMichele, Angela, Van’t Veer, Laura, McCarthy, Nicole, Sinn, Bruno V., Gelmon, Karen, García-Sáenz, José Ángel, Kelly, Catherine M., Reimer, Toralf, Turner, Nicholas, Rojo, Federico, Filipits, Martin, Fasching, Peter A., Schem, Christian, Martin, Lesley-Ann, Liu, Yuan, Toi, Masakazu, Rugo, Hope, Gnant, Michael, Makris, Andreas, Furlanetto, Jenny, Weber, Karsten, Denkert, Carsten, Loibl, Sibylle
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.SABCS22-PD17-06

Background: The Penelope-B trial did not show improvement in invasive disease-free survival (iDFS) with the addition of palbociclib to endocrine therapy (ET) in patients with high-risk early breast cancer (BC) after neoadjuvant chemotherapy (NACT). Biomarkers may be able to identify subgroups of patients deriving benefit from Palbociclib and guide future studies. Estrogen-receptor (ER), progesterone-receptor (PgR) and Ki-67 might be helpful in identifying patients benefiting from palbociclib. Concordantly, tumors with elevated expression of Cyclin D1 and phosphorylated retinoblastoma protein (phospho-RB) may harbor more dependency on CDK4/6 and thus higher sensitivity to palbociclib. Methods: The percentage of positive ER and PgR cells and Ki-67 assessed in surgical specimens after NACT were combined to obtain the immunohistochemical score 3 (IHC3, Cuzick et al JCO 2011, low vs high based on the median IHC3 value). Cyclin D1 and phospho-RB Ser 807/811 immunoreactive (phospho-RB) scores were analyzed in residual tumors after NACT (range 0-12 each). Proportional hazard regression model was used to assess the predictive and prognostic value of IHC3 and treatment on iDFS. Subgroup analysis was performed according to BC intrinsic subtypes (luminal-A/normal-like, luminal-B/HER2-enriched/basal) and HER2-status (HER2 0, HER2 low). Cox/Fine-Gray regression was used to define the predictive and prognostic value of CyclinD1 (≤1, >1), phospho-RB (≤2, >2) as dichotomized and continuous variables on iDFS, distant DFS (DDFS), locoregional invasive recurrence-free interval (LRRFI) and overall survival (OS). Multivariate analyses (MVA) were adjusted for age (≤50 vs >50), Ki-67 (≤15 vs >15), region (non-Asian vs Asian), ypN (ypN0-1 vs ypN2-3), risk status (CPS-EG=2 ypN+ vs ≥3), cT (cT1-2 vs cT3-4), ypT (ypT0-2 vs ypT3-4), and grade (G1-2 vs G3). The MVA for IHC3 includes all the covariates above except Ki-67. p< 0.05 was defined as statistically significant. Results: Data for ER, PgR, Ki-67, HER2, Cyclin D1 and phospho-RB were available for 1250 patients. Overall, 98.9% of the patients had ER+ tumors, 75.0% PgR+, 52.2% had HER2 low, 25.5% Ki-67>15, 50% had IHC3 score higher than median, 93.9% had Cyclin D1 >1, 57.8% had phospho-RB >2. Patients with IHC3 score high had a worse iDFS compared to patients with IHC3 score low (MVA HR 2.28 95%CI (1.78-2.91), p< 0.0001). Patients with luminal-A/normal-like tumors and IHC3 low had an improved iDFS with the addition of palbociclib t