Residual Cancer Burden Class Research Articles

Abstract S6-02: Long-term prognostic value of residual cancer burden (RCB) classification following neoadjuvant chemotherapy

Abstract Background: In 2007 we described residual cancer burden (RCB) as a measure of pathologic response after neoadjuvant chemotherapy and demonstrated that RCB was strongly prognostic for 5-year survival outcomes. Herein, we update the long-term outcome of this original cohort, validate our results in an independent patient group, and report outcome according to hormone receptor (HR) and HER2 receptor status. Methods: Our original RCB development cohort received paclitaxel followed by fluorouracil, doxorubicin and cyclophosphamide (T/FAC) and the original validation cohort received FAC alone as neoadjuvant chemotherapy for stage II or III breast cancer (JCO 2007;25:4414-22). We subsequently evaluated RCB in 2008 in another independent validation cohort of patients treated with neoadjuvant T/FAC. These patient cohorts were followed up until 2013. The T/FAC cohorts were combined to test RCB within phenotypic subsets of HER2+, HR+/HER2-, and triple receptor-negative breast cancer (TNBC). Pre-defined RCB classes of pathologic complete response (pCR), minimal (RCB-I), moderate (RCB-II) and extensive (RCB-III) residual disease were compared with respect to relapse-free survival (RFS) using the likelihood ratio test and estimates of 10-year RFS (with 95% confidence interval) were determined from Kaplan-Meier analysis. We excluded patients with HER2-positive (HER2+) cancer who received neoadjuvant or adjuvant trastuzumab. Results: Median follow up of event-free survivors was 142 months for the original T/FAC development cohort (N = 220), 91 months for the T/FAC validation cohort (N = 277), and 198 months for the FAC (N = 169) cohort. The estimates of 10-year RFS by RCB class for each cohort, respectively, were 86%, 81% and 95% for pCR; 87%, 81% and 85% for RCB-I; 76%, 62%, and 62% for RCB-II; and 38%, 36% and 38% for RCB-III. Table 1 presents the frequency and the estimates of 10-year RFS for each RCB class within each phenotypic subset of breast cancer (HER2+, TNBC, and HR+/HER2-) in the combined T/FAC cohorts (N = 497). Frequency and estimated 10-year RFS of RCB classes in breast cancer subsets after T/FAC chemotherapy HER2+TNBCHR+/HER2-RCB ClassFreqRFS (95% CI)FreqRFS (95% CI)FreqRFS (95% CI)pCR36%83% (66 to 92)35%82% (63 to 92)10%83% (59 to 93)RCB-I16%69% (41 to 86)15%82% (53 to 94)13%96% (74 to 99)RCB-II30%50% (31 to 66)33%54% (38 to 68)60%76% (68 to 83)RCB-III18%32% (13 to 52)17%18% (6 to 36)17%45% (27 to 61)RFS, relapse-free survival; Freq, frequency; CI, confidence interval. RCB was prognostic in all cohorts and subgroups (p<0.001). The hazard rate (per year) associated with RCB-III and RCB-II was highest during the first 3 years for HER2+ and TNBC but was similar to pCR/RCB-I beyond 6 years. However, for HR+/HER2- cancers the annual hazard rate was consistent during the first decade, at 6%-8% for RCB-III and 2% for RCB-II. Conclusions: RCB after neoadjuvant chemotherapy was strongly prognostic in all phenotypic subsets of breast cancer patients over a decade of follow up, even for HR+/HER2- cancers. In HER2-negative breast cancers, RCB-I had similar prognosis to pCR, whereas RCB-III for HR+/HER2- and RCB-II/III for TNBC defined high-risk patient populations following neoadjuvant chemotherapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S6-02.

Abstract P3-14-15: Nabrax: Neoadjuvant therapy of breast cancer with weekly nab-paclitaxel: Final safety of GEICAM 2011-02

Abstract Aims: nab-paclitaxel is an innovative chemotherapy that consists of nano-particles of human serum albumin bound paclitaxel. It exploits the role of albumin as the natural carrier of hydrophobic molecules in human to increase paclitaxel delivery to tumor cells. Weekly nab-paclitaxel showed a superior efficacy compared to every 3-weeks docetaxel in a randomized phase II study in metastatic breast cancer (Gradishar JCO 2009, Clin. Breast Cancer 2012). This single arm phase II trial has been designed to evaluate the activity and safety of weekly nab-paclitaxel as neoadjuvant treatment of early stage breast cancer patients with positive estrogen receptors and negative HER2. Methods: Stage II-III patients were included and treated with nab-paclitaxel weekly at a dose of 150 mg/m2 on days 1, 8 and 15 every 4 weeks for 4 cycles. Following chemotherapy, patients undergo surgery and adjuvant therapy (with radiation, chemo and endocrine therapy) under the investigator criteria. The primary objective is to determine the residual cancer burden class III as measured by the Symmans criteria (JCO 25:4422,2007). Secondary objectives include pathological complete response, overall response, invasive disease free survival, safety and potential correlative biomarkers. Results: Eighty-three patients have been recruited in the study in 13 Spanish institutions. Here we report safety data from 77 patients. Median age was 48 years, 62% were postmenopausal and 94% had ECOG PS 0; most patients were stage II (23% IIa and 36% IIb). A total of 259 cycles have been administered to date; 47 patients completed 4 cycles as planned, 5 patients discontinued treatment early (due to grade 2-3 sensory neuropathy in 4 patients), the remaining patients are still under treatment. The treatment was delayed in 8.1% of patients; nab-paclitaxel doses were omitted and reduced in 3.9% and 9.7% of cycles respectively, for a relative dose intensity of nab-paclitaxel of 97.3%. The most frequent reasons for dose modifications were neutropenia (5.4%) and neuropathy (2.7%). The main grade 2/3 adverse events are described in table 1. Table 1Related adverse events.Per patient (N = 74)Per Cycle (N = 259)NCI-CTCAE vs 4.0. (>5% grade 2-4)Grade 2, N (%)Grade 3, N (%)Grade 2, N (%)Grade 3, N (%)Leukopenia6 (8.1)1 (1.4)11 (4.2)1 (0.4)Neutropenia17(23)7 (9.5)30 (11.6)9 (3.5)Alopecia47(63.5)—121 (46.7)—Fatigue11 (14.9)2 (2.7)17 (6.6)2 (0.8)Neuropathy: Sensory17 (23)2 (2.7)25(9.6)5 (1.9)Musculoskeletal Pain11 (14.9)0 (0)13 (5.0)0 (0) Conclusions: Neoadjuvant therapy with weekly nab-paclitaxel at dose of 150 mg/m2 on days 1, 8 and 15 every 4 weeks was well tolerated. Final safety data for the entire treated patients will be mature and presented at the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-15.

Multicenter phase II trial of neoadjuvant carboplatin, weekly nab-paclitaxel, and trastuzumab in stage II-III HER2+ breast cancer: A BrUOG study.

619 Background: Patients (pts) with human epidermal growth factor receptor-2 amplified (HER2+) breast cancers (BrCa) who achieve a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) + trastuzumab (T) have an excellent prognosis (Cortazar, SABCS 2012). We tested a novel NAC + T regimen, designed to avoid potential cardiac and other toxicities associated with anthracyclines (A) and eliminate steroid premedication by replacing standard paclitaxel with nab-paclitaxel (nP). Methods: Clinical stage IIA-IIIC HER2+ BrCa pts received single agent either nP or T, with research biopsies and MRIs obtained before and after, then carboplatin (Cb) AUC 6 q3wks, nP 100 mg/m2and T 2 mg/kg weekly x 18 wks. If present, residual tumor was collected at surgery. Post-op pts complete a year of T; other adjuvant treatment is at MD discretion. Endpoints include clinical + pathologic response (pCR is defined as no invasive BrCa in breast + axillary nodes), residual cancer burden (RCB), treatment delivery and toxicities. Results: 53 pts (of 60 planned) are evaluable for response, median age 51 (34-72). Median delivered dose intensity for nP was 89 mg/m2/week; nP doses were omitted or reduced for neutropenia (ANC) (in 20% of pts) and neurotoxicity (Nt) (5%). Cb was reduced for thrombocytopenia (tcp) in 15%. Grade 3-4 toxicities: ANC 65%, tcp 22%, anemia 37%, Nt 7%. Serious adverse events: febrile neutropenia (5 pts), infections w/o neutropenia (4), vomiting, diarrhea or dehydration (7), thrombosis (2). LVEF fell by >10% in 3 pts with no clinical CHF. Response data are tabulated below: 28 pts (53%) achieved pCR or RCB class I; 15/21 who did not received A-based adjuvant chemotherapy. Of 38 clinically node-positive pts, 26 (68%) were node-negative at surgery. Conclusions: The Cb/nP/T regimen was well tolerated, with pCR rates comparable to those reported with A-containing regimens. Final treatment and response data will be presented; correlative studies will be reported separately. Clinical trial information: NCT00617942. [Table: see text]

Respuesta patológica a la quimioterapia neoadyuvante: correlación entre 2 sistemas de gradación histológica

ObjectiveTo determine the variability between 2 grading systems in the classification of pathologic response to neoadjuvant chemotherapy in the same lesion. Material and methodsFifty-one patients with invasive breast cancer were consecutively treated with neoadjuvant chemotherapy in an 8-year period. Pathologic response in each patient was established according to the Miller and Payne (MP) and the residual cancer burden (RCB) systems and the results were correlated. ResultsIn the MP system, the lesions were classified in grade 1 (6%), 2 (25%), 3 (27%), 4 (27%) and 5 (14%). RCB class was 0 (13%), I (13%), II (54%) and III (20%). The correlation between MP 5 and RCB 0, between MP 4 and RCB I, and between MP 2 and RCB III was good. There were more discrepancies between MP 1, 2, 3 and RCB II. ConclusionsThe correlation between the 2 grading systems is good. There are discrepancies in the assessment of lack of response between the 2 systems. This disagreement could be due to the inclusion of lymph node status in the RCB system.

Abstract P4-02-07: Early Optical Tomography Changes Predict Breast Cancer Response to Neoadjuvant Chemotherapy

Abstract Background: Pathologic complete response (pCR) or a low Residual Cancer Burden (RCB) score following neoadjuvant chemotherapy (NACT) predicts a superior survival in breast cancer (BC) patients. An early predictive marker of tumor response during NACT would provide a way to optimize treatment for non-responders; however, no ideal technology currently exists. Diffuse optical tomography (DOT) is a novel, fast, safe, and low-cost technique that uses near infrared light to provide 3D data on tissue vascularity without the use of radiation, making it a promising technology for assessing early tumor response to NACT. We hypothesized that a 2-week change in DOT parameters would predict response to NACT as measured by the RCB score. Methods: Women with stage II-IIIc invasive BC scheduled to undergo NACT with 12 cycles of a weekly taxane followed by 4 cycles of doxorubicin with cyclophosphamide (AC) were enrolled. Treatment with additional biologic therapies was allowed. DOT measurements were made before starting NACT, 2 weeks into treatment, and before surgery. Concentrations of oxyhemoglobin [HbO2], deoxyhemoglobin [Hb], total hemoglobin [HbT], and tissue scattering (SC) were measured by DOT. Final pathology specimens were scored for the RCB index (continuous measure), RCB class (0, 1, 2, 3), and a dichotomized RCB score (RCB class 0 or 1: responders to NACT; RCB class 2 or 3: non-responders). Correlation analysis, ANOVA testing, and two sample t-tests were used to evaluate the relationship between the two-week changes in DOT parameters and the RCB score. Results: Since July 2011, we have recruited 11 pts, of whom 7 have undergone surgery. Complete data is available for 6 pts. Two of 7 pts had a pCR (RCB 0), 1 had RCB 1, 3 had RCB 2, and 1 had RCB 3. The Pearson correlation between the 2-week change in [Hb] and the continuous RCB index was 0.94 (p = 0.0047), and that between the 2-week change in SC and the RCB index was 0.93 (p = 0.0073). At 2 weeks, the [Hb] decreased by 6.7% for pts whose pathology demonstrated an RCB 0 (pCR), 1.8% for RCB 1, 0.6% for RCB 2, and increased 0.7% for RCB 3. ANOVA and Tukey testing demonstrated a significant difference in the [Hb] change for pts with RCB 0 compared to pts with RCB 1, 2, or 3 (p <0.05). At 2 weeks, SC decreased by 26.5% for pts with RCB 0, 19.3% for RCB 1, 3.7% for RCB 2, and increased by 25.1% for RCB 3. There was a significant difference in the SC change for pts with RCB 0 compared to pts with RCB 3 (p <0.05). Responders (RCB 0/1) had a 5% decrease in [Hb] at 2 weeks compared to non-responders (RCB 2/3) who had a decrease in 0.18% in [Hb] (p = 0.0045), and responders had a 24% decrease in SC compared to non-responders who had an increase in 6% (p = 0.044). Conclusions: DOT change is an early predictor of response to NACT as measured by the RCB score. We found a significant linear association between the RCB index and the 2-week change in [Hb] and SC. Significantly different changes in DOT parameters were associated with the other RCB classifications. Additional recruitment is ongoing and differences by tumor subtype will be evaluated. *These two authors contributed equally to this study Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-02-07.

Pathologic Tumor Response of Invasive Lobular Carcinoma to Neo-adjuvant Chemotherapy

Neo-adjuvant chemotherapy is used for locally advanced breast cancer patients with significant variation in tumor response. Our objective is to determine the clinicopathologic effect of neo-adjuvant chemotherapy on invasive lobular carcinoma. A review of a single-institution data base of women diagnosed with breast cancer identified 30 patients from 1999 to 2009 with operable invasive lobular carcinoma who received neo-adjuvant chemotherapy. Patient demographics and clinicopathologic data were reviewed. Cases were reviewed by a single pathologist (NNE). Residual cancer burden class was determined for each case. Median patient age was 50 years (range 25-79). All tumors were hormone receptor positive and clinical stage II or III carcinomas. Most patients (53.3%) had combination anthracycline- and taxane-based chemotherapy. Therapy-related changes were noted within the tumor bed in 25 (83.3%) patients. Six (30%) of 20 patients with residual axillary disease had therapy-related nodal changes. There were 11 patients with moderate residual disease (class II) and 18 (60%) with extensive (class III); there were no complete pathologic responses (class 0). Only one patient (3.3%) converted from mastectomy to breast-conserving surgery. Four (13.3%) patients developed distant metastases; all had pleomorphic-type, clinical stage III tumors with residual cancer burden III classification and developed distant disease in the 2 years after surgery (range 0-26 months). Median follow-up time was 29.5 months (range 7-132). Patients with locally advanced pleomorphic-type lobular carcinoma appear to develop early post-treatment metastatic disease. Neo-adjuvant chemotherapy did not appear to have significant impact on the surgical treatment of patients with invasive lobular carcinoma.

Prognostic value of residual cancer burden after neoadjuvant taxane-anthracycline chemotherapy in phenotypic subsets of breast cancer

544 Background: The aim of this study was to evaluate the prognostic strength of residual cancer burden (RCB) measurements according to tumor phenotype in patients who were uniformly treated with neoadjuvant chemotherapy. Methods: We studied 559 patients who received paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide (T/FAC) as neoadjuvant chemotherapy, including 241 previously reported and 318 new cases. No patients received any trastuzumab therapy. RCB index was determined from retrospective pathologic review of the surgical resection specimen (www.mdanderson.org/breastcancer_RCB). Tumor phenotype was determined by standard tests for HER2 status, then estrogen receptor (ER) status, and categorized as: HER2+, ER+/HER2-, or ER-/HER2-. Association of RCB with distant relapse-free survival (DRFS) was evaluated using Kaplan-Meier (log-rank test) and Cox regression analyses. Results: RCB was significantly associated with DRFS in both the original and new cohorts (median follow-up 79 months and 31 months, respectively), and in each phenotypic group (Table). DRFS was identical for RCB-0 and RCB-I. RCB was significantly prognostic (HR 2.08, 95% CI 1.74–2.52, P<0.0001) in multivariate analysis after adjusting for phenotype (P=0.0004), age dichotomized at 50 (P=0.03), clinical Stage at diagnosis (P=0.11), and use of adjuvant hormone therapy (P=0.08). Conclusions: Residual cancer burden after neoadjuvant T/FAC chemotherapy is strongly prognostic in all phenotypic subsets of breast cancer. Number RCB Index (continuous) RCB Classes (0-III) HR (95% CI) P value Log-rank test (P value) Original cohort 241 1.82 (1.42–2.39) < 0.0001 < 0.0001 New cohort 318 1.74 (1.40–2.19) < 0.0001 < 0.0001 HER2+ 142 (25%) 1.86 (1.45–2.41) < 0.0001 < 0.0001 ER+/HER2- 256 (46%) 1.80 (1.26–2.66) 0.0009 0.002 ER-/HER2- 161 (29%) 2.35 (1.80–3.14) < 0.0001 < 0.0001 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Nuvera Biosciences, Inc. Nuvera Biosciences, Inc. Nuvera Biosciences, Inc.

Thirty-Gene Pharmacogenomic Test Correlates with Residual Cancer Burden after Preoperative Chemotherapy for Breast Cancer

We examined whether the response predicted by a 30-gene pharmacogenomic test correlated with the residual cancer burden (RCB) after preoperative chemotherapy with paclitaxel, 5-fluorouracil, doxorubicin, and cyclophosphamide (T/FAC). Gene expression profiling was done at diagnosis in 74 patients with stages I to III breast cancer and was used to calculate a pharmacogenomic score and predict response to chemotherapy [pathologic complete response (pCR) or residual disease (RD)]. All patients received 6 months of preoperative T/FAC. Following pathologic review, a RCB score was calculated based on residual tumor and lymph node features. Four RCB classes were assigned; RCB-0 (pCR), RCB-I (near-PCR), RCB-II (moderate RD), and RCB-III (extensive RD). The correlations between the pharmacogenomic score, predicted pathologic response, RCB score, and RCB class were examined. Thirty-three patients were predicted to have pCR, and 40 were predicted to have RD. Observed responses were RCB-0: n=20 (27%); RCB-I: n=5 (7%); RCB-II: n=36 (49%); and RCB-III: n=13 (16%) patients. Pharmacogenomic and RCB scores were correlated (Pearson's R=-0.501, P<0.0001). There was no difference between the mean genomic predictor scores for RCB-0/I groups (P=0.94), but these were different from the mean scores of the RCB-II/III groups (P<0.001). Among the 25 patients with RCB-0/I response, 19 (76%) were predicted to achieve pCR. The pharmacogenomic test correctly predicted RD in 92% of the patients with RCB-III, which corresponds to chemotherapy-resistant disease. The 30-gene pharmacogenomic test showed good correlation with the extent of residual invasive cancer burden measured as both continuous and categorical variables.