Prognostic Value of Residual Disease Burden Appears Consistent in Early Breast Cancer Regardless of Disease Subtype


Patients with early breast cancer appear to have consistent prognostic value associated with residual cancer burden, regardless of disease subtype.

The prognostic value of residual cancer burden (RCB) appeared to remain consistent for patients with stage II/III breast cancer who received neoadjuvant therapy regardless of disease subtype and therapy, according to the results of an analysis of the phase 2 I-SPY2 trial (NCT01042379).

Event-free survival (EFS) was reported to significantly worsen per unit of RCB across all breast cancer subtypes, including hormone receptor (HR)–positive/ERBB2-negative (HR, 1.75; 95% CI, 1.45-2.16), HR-positive/ERBB2-positive (HR, 1.55; 95% CI, 1.18-2.05), HR-negative/ERBB2-positive (HR, 2.39; 95% CI, 1.64-3.49), and HR-negative/ERBB2-negative (HR, 1.99; 95% CI, 1.71-2.31).

“To our knowledge, this is the first reported comparison of continuous RCB distributions between treatments in a randomized clinical trial,” the investigators wrote. “Quantitative assessment of residual disease using the RCB method was generalizable across a network of clinical trial sites and provided prognostic information in all subtypes of breast cancer. Prognostic surrogacy of RCB was irrespective of neoadjuvant treatment and provides an assessment of residual risk that appears to be clinically meaningful and could inform a patient’s subsequent adjuvant treatment.”

The analysis is reflective of the pathologic complete response analysis of 10 therapies that were evaluated in patients at high risk of early recurrence who were treated as part of the I-SPY2 platform trial. In addition to including the same participants and treatment arms, the analysis also featured longer follow up. In the control arm for patients with ERBB2-negative disease, therapy involved weekly paclitaxel followed by doxorubicin and cyclophosphamide every 2 to 3 weeks versus different investigational treatments there were combined with weekly paclitaxel. For patients with ERBB2-positive cancer, treatment in the control arm consisted of weekly paclitaxel plus trastuzumab (Herceptin) and doxorubicin and cyclophosphamide every 3 weeks. Enrollment to the trastuzumab control group ended in 2014 following the accelerated approval of pertuzumab (Perjeta) plus docetaxel and trastuzumab followed by neoadjuvant doxorubicin/cyclophosphamide.

Graduation was considered in 4 phenotypic subtypes that were defined by receptor status, including HR-positive/ERBB2-negative, HR-negative/ERBB2-negative, HR-positive/ERBB2-positive, and HR-negative/ERBB2-positive disease. Among these subtypes, pembrolizumab (Keytruda) graduated to further examination in HR-positive/ERBB2-negative; veliparib (ABT-888), carboplatin, and pembrolizumab graduated in HR-negative/ERBB2-negative; ado-trastuzumab emtansine (T-DM1; Kadcyla) plus pertuzumab (Perjeta) and pertuzumab, docetaxel, and trastuzumab graduated in HR-positive/ERBB2-positive; and neratinib (Nerlynx), MK2206, T-DM1, plus pertuzumab as well as pertuzumab plus docetaxel and trastuzumab graduated in HR-negative/ERBB2-positive disease.

Treatments that completed accrual but did not graduate across any subtype included AMG386 (trebananib), ganitumab, and ganetespib. Treatment with pexidartinib was discontinued due to safety concerns following the accrual of 9 patients and was subsequently excluded from the analysis. Therapeutic regimens were broken up into several categories based on their efficacy, including the control arm, investigational regimens that graduated, and investigation regimens that did not graduate.

A total of 98.7% of the 950 eligible patients received surgical resection following treatment with neoadjuvant chemotherapy and RCB evaluation. Notably, some patients did not go on to receive surgery due to disease progression (n = 6), withdrawal (n = 2), refusal of surgery (n = 2), or for another reason (n = 2). Of 938 patients, 38% were HR-positive/ERBB2-negative, 34% were HR-negative/ERBB2-negative, 18% were HR-positive/ERBB2-positive, and 9% were HR-negative/ERBB2-positive. Twenty-one percent of patients in the control arm received neoadjuvant chemotherapy, 27% were given an investigational therapy that graduated in their disease subtype, and 52% received an investigational therapy that did not graduate in their subtype.

Additional findings from the trial indicated that the prognostic significance of RCB was identified that appeared similar across groups of treatment that graduated (HR, 2.00; 95% CI, 1.57-2.55), did not graduate (HR, 1.87; 95% CI, 1.61-2.17), and the control arm (HR, 1.79; 95% CI, 1.42-2.26).

Moreover, investigational therapies were found to significantly lower RCB in patients with HR-negative/ERBB2-negative disease who received graduated and nongraduated treatments. Similar findings were observed for ERBB2-positive subtypes who received a graduated treatment, experiencing improved EFS (HR, 0.61; 95% CI, 0.41-0.93).


Symmans WF, Yau C, Chen YY, et al. Assessment of residual cancer burden and event-free survival in neoadjuvant treatment for high-risk breast cancer an analysis of data from the I-SPY2 randomized clinical trial. JAMA Oncol. Published online September 16, 2021. doi:10.1001/jamaoncol.2021.3690

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