Pathologic complete response (pCR) rates for patients with HR+/HER2- high-risk, early-stage breast cancer (EBC) by clinical and molecular features in the phase II I-SPY2 clinical trial

Abstract

Background: Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer (EBC) is a heterogenous disease. Identification of better clinical and molecular biomarkers is essential to guide optimal therapy for each patient.

Patients and methods: We analyzed rates of pathologic complete response (pCR) and distant recurrence-free survival (DRFS) for patients with HR+/HER2-negative EBC in eight neoadjuvant arms in the I-SPY2 trial by clinical/molecular features: age, stage, histology, percentage estrogen receptor (ER) positivity, ER/progesterone receptor status, MammaPrint (MP)-High1 (0 to -0.57) versus MP-High2 (<-0.57), BluePrint (BP)-Luminal-type versus BP-Basal-type, and ImPrint immune signature. We quantified the clinical/molecular heterogeneity, assessed overlap among these biomarkers, and evaluated associations with pCR and DRFS.

Results: Three hundred and seventy-nine patients with HR+/HER2-negative EBC were included in this analysis, with an observed pCR rate of 17% across treatment arms. pCR rates were higher in patients with stage II versus III disease (21% versus 9%, P = 0.0013), ductal versus lobular histology (19% versus 11%, P = 0.049), lower %ER positivity (≤66% versus >66%) (35% versus 9%, P = 3.4E-09), MP-High2 versus MP-High1 disease (31% versus 11%, P = 1.1E-05), BP-Basal-type versus BP-Luminal-type disease (34% versus 10%, P = 1.62E-07), and ImPrint-positive versus -negative disease (38% versus 10%, P = 1.64E-09). Patients with lower %ER were more likely to have MP-High2 and BP-Basal-type disease. At a median follow-up of 4.8 years, patients who achieved pCR had excellent outcomes irrespective of clinical/molecular features. Among patients who did not achieve pCR, DRFS events were more frequent in patients with MP-High2 and BP-Basal-type disease than those with MP-High1 and BP-Luminal-type disease.

Conclusions: Among patients with high molecular-risk HR+/HER2-negative EBC, the MP-High2, BP-Basal-type, and ImPrint-positive signatures identified a partially overlapping subset of patients who were more likely to achieve pCR in response to neoadjuvant chemotherapy ± targeted agents or immunotherapy compared to patients with MP-High1, BP-Luminal-type, and ImPrint-negative disease. I-SPY2.2 is incorporating the use of these biomarkers to molecularly define specific patient populations and optimize treatment selection.

Keywords: MammaPrint; basal; intrinsic subtype; luminal; molecular subtype; neoadjuvant therapy.

Figure 1.. I-SPY2 trial schema and pCR rate among patients with high-risk early-stage HR+/HER2− breast cancer in eight arms of the I-SPY2 trial included in this analysis.

(A) This diagram depicts the I-SPY2 trial schema. The investigational arms included in this analysis are shown in blue in the box below the schema. (B) Distribution of breast cancer receptor subtypes among the first 987 patients enrolled in the I-SPY2 trial is shown in the left. This paper focuses on the 379 patients (38%) who have HR+/HER2− disease. Of the patients with HR+/HER2− disease, the percentage of patients who achieved a pCR is shown in the right by treatment arm with the pCR rate listed above each bar. HR, hormone receptor; HER2, human epidermal growth factor receptor 2; HSP90, heat shock protein 90; IGF-1R, insulin-like growth factor 1 receptor; MRI, magnetic resonance imaging; PARPi, poly (ADP-ribose) polymerase inhibitor; pCR, pathologic complete response; PD-1, programmed cell death protein 1; TKI, tyrosine kinase inhibitor; TNBC, triple-negative breast cancer.

Figure 2.. Observed pathologic complete response rate by stage, histology, ER% positivity, ER/PR status, and age.

Mosaic plots showing the percentage of patients who achieved pCR (dark purple) versus non-pCR (light purple) by: (A) clinical stage: stage II versus III disease; (B) histology: IDC versus ILC versus mixed ILC/IDC; (C) ER % positivity: ER ≤10% (low) versus ER 11%−66% (intermediate) versus ER >66% (high); (D) ER/PR status: ER−PR+ versus ER+PR− versus ER+PR+; and (E) dichotomized age: ≤ 40 years versus >40 years. ER, estrogen receptor; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; pCR, pathologic complete response; PR, progesterone receptor.

Figure 3.. Observed pathologic complete response rate by MammaPrint, BluePrint, and ImPrint status.

Three-way Sankey diagram depicting the association between MammaPrint (MP)-High1 (pink) versus MP-High2 (red), BluePrint (BP)-Luminal-type (light blue) versus BP-Basal-type (dark blue), and ImPrint negative (light green) versus Imprint positive (dark green). The observed pCR rate by treatment arm for each of these molecular features is shown in boxes, with the pCR rate per treatment arm listed above each bar. pCR, pathologic complete response.

Figure 4.. Correlation between ER% positivity, ER/PR status, and age with molecular features.

Bar plots of the frequency of patients with MammaPrint (MP)-High1 (pink) versus MP-High2 (red), BluePrint (BP)-Luminal-type (light blue) versus BP-Basal-type (dark blue), and ImPrint negative (light green) versus ImPrint positive (dark green) within subsets defined by (A) ER% positivity: ≤10% (low), 11%−66% (intermediate), >66% (high); (B) ER/PR status: ER−PR+, ER+PR−, ER+PR+; (C) dichotomized age: age ≤ 40 years, age > 40 years. ER, estrogen receptor; PR, progesterone receptor.

Figure 5.. Distant recurrence-free survival (DRFS) by pCR status and by molecular features in patients with non-PCR with a median follow-up of 4.8 years.

(A) DRFS at median 4.8 years of follow-up in patients who achieved a pCR (dark purple) versus patients who did not achieve a pCR (non-PCR) (light purple). (B-D) Among patients who did not achieve a pCR, DRFS at median 4.8 years of follow-up by: (B) MammaPrint (MP)-High1 (pink) versus MP-High2 (red), (C) BluePrint (BP)-Luminal-type (light blue) versus BP-Basal-type (dark blue), and (D) ImPrint-negative (light green) versus Imprint-positive (dark green). DRFS, distant recurrence-free survival; HR, hormone receptor; HER2, human epidermal growth factor receptor 2; pCR, pathologic complete response.