Low Estrogen Receptor (ER)-Positive Breast Cancer and Neoadjuvant Systemic Chemotherapy: Is Response Similar to Typical ER-Positive or ER-Negative Disease?

OBJECTIVES: Pathologic complete response (pCR) rate after neoadjuvant chemotherapy was compared between 141 estrogen receptor (ER)-negative (43%), 41 low ER+ (13%), 47 moderate ER+ (14%), and 98 high ER+ (30%) tumors. METHODS: Human epidermal growth factor receptor 2-positive cases, cases without semiquantitative ER score, and patients treated with neoadjuvant endocrine therapy alone were excluded. RESULTS: The pCR rate of low ER+ tumors was similar to the pCR rate of ER- tumors (37% and 26% for low ER and ER- respectively, P = .1722) but significantly different from the pCR rate of moderately ER+ (11%, P = .0049) and high ER+ tumors (4%, P < .0001). Patients with pCR had an excellent prognosis regardless of the ER status. In patients with residual disease (no pCR), the recurrence and death rate were higher in ER- and low ER+ cases compared with moderate and high ER+ cases. CONCLUSIONS: Low ER+ breast cancers are biologically similar to ER- tumors. Semiquantitative ER H-score is an important determinant of response to neoadjuvant chemotherapy.

Prognostic Significance of Modified Residual Disease in Breast and Nodes (mRDBN) Algorithm After Neoadjuvant Chemotherapy for Breast Cancer.

OBJECTIVES: We hypothesized that prognostic accuracy of the residual disease in breast and lymph nodes (RDBN) method, which is calculated using residual tumor size, nodal involvement, and tumor grade, may be improved by incorporating residual tumor cellularity. METHODS: Cases included 614 patients who underwent neoadjuvant therapy for breast cancer. Tumor size was adjusted for residual cellularity of invasive carcinoma and used to calculate modified RDBN (mRDBN) and compared with unmodified gross tumor size (gRDBN). RESULTS: RDBN could be calculated in 428 cases. Relative risks of recurrence and death were significantly higher for RDBN-3 and RDBN-4 compared with RDBN-1. Kaplan-Meier analysis showed significant differences in disease-free survival and overall survival for estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative and ER-positive/HER2-negative subgroups (P < .0001). CONCLUSIONS: Both mRDBN and gRDBN provide prognostic information, particularly in HER2-negative carcinoma; however, mRDBN showed better stratification of RDBN-3 and RDBN-4 patients.

Characterizing Molecular Variants and Clinical Utilization of Next-generation Sequencing in Advanced Breast Cancer.

Women with advanced breast carcinomas have few therapeutic options. Recent advances in genomic profiling represent a new paradigm of cancer classification and treatment, but experience with genomic testing in a clinical setting remains limited. We retrospectively determined the genomic variants and correlate these with histology [histomorphologic subtype, nuclear grade, standard immunohistochemistry (IHC)] and clinical utilization (ordering, turnaround time, report review, and targeted therapy). Among 48 patients, 2 showed no genetic alterations, 11 (23%) showed variants of unclear significance only and 35 (73%) showed variant(s) affecting function (VaF) and/or variants of unclear significance. Overall, 119 variants were observed in 20 of 50 tested genes. Each patient had a unique molecular profile, with numerous (n=58) variants not previously reported in breast cancer. VaF detected in more than 2 patients included: TP53 (n=21), PIK3CA (n=20), and FGFR1 (n=3). VaF comprised 46 single nucleotide variants (79%), 7 amplifications (12%), 3 frameshifts (5%), 1 insertion (2%), and 1 deletion (2%). The tested samples had very high Ki67 index (average 57%±23%) and approximately half were hormone receptor and HER2 negative (25/46, 54%). Metastatic breast carcinomas showed a higher average VaF versus breast-localized tumors (1.3±0.99 vs. 0.18±0.60, P<0.05). Next-generation sequencing reports were promptly reported and reviewed (average 1 to 2 d) and 7 (∼25%) of potentially eligible patients received targeted therapy. Advanced breast cancers show unique landscapes of genetic variants. Most testing was done in late disease, often in metastatic and receptor-negative carcinomas. Next-generation sequencing results were promptly reported and reviewed, but the utilization of targeted therapies was limited.

Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for human epidermal growth factor receptor 2 positive locally recurrent or metastatic breast cancer: results from a Phase II, single-arm, multicenter study.

Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for the treatment of patients with metastatic breast cancer who previously received ≥2 chemotherapy regimens in the metastatic setting. Primary data from a Phase II trial for the first-line combination of eribulin plus trastuzumab in human epidermal growth factor receptor 2 positive patients showed a 71% objective response rate and tolerability consistent with the known profile of these agents. Here, we present prespecified analyses of efficacy of this combination based on prior trastuzumab use. Patients received eribulin mesylate 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) intravenously on days 1 and 8 plus trastuzumab (8 mg/kg intravenously/cycle 1, then 6 mg/kg) on day 1 of each 21-day cycle. Objective response rates, progression-free survival, and tolerability were assessed in patients who had and had not received prior adjuvant or neoadjuvant (neo/adjuvant) trastuzumab treatment. Fifty-two patients (median age: 59.5 years) received eribulin/trastuzumab for a median treatment duration of ~31 weeks; 40.4% (n=21) had been previously treated with neo/adjuvant trastuzumab prior to treatment with eribulin plus trastuzumab for metastatic disease (median time between neo/adjuvant and study treatment: 23 months). In trastuzumab-naïve patients (n=31) compared with those who had received prior trastuzumab, objective response rate was 77.4% versus 61.9%, respectively; duration of response was 11.8 versus 9.5 months, respectively; clinical benefit rate was 87.1% versus 81.0%, respectively; and median progression-free survival was 12.2 versus 11.5 months, respectively. The most common grade 3/4 treatment-emergent adverse events (occuring in ≥5% of patients) in patients who received prior trastuzumab versus trastuzumab naïve patients, respectively, were neutropenia (47.6% vs 32.3%), peripheral neuropathy (14.3% vs 25.8%), febrile neutropenia (14.3% vs 3.2%), fatigue (9.5% vs 6.5%), nausea (9.5% vs 0%), vomiting (9.5% vs 3.2%), and leukopenia (9.5% vs 3.2%). In patients with human epidermal growth factor receptor 2 positive metastatic breast cancer, first-line eribulin/trastuzumab treatment demonstrated substantial antitumor activity and was well tolerated, regardless of prior neo/adjuvant trastuzumab treatment.

Pathways Clinical Decision Support for Appropriate Use of Key Biomarkers.

PURPOSE: Breast cancer diagnostics have the ability to predict disease recurrence and the benefit of chemotherapy. This study measures the use of a diagnostic assay, Oncotype DX, when embedded in a breast cancer decision support algorithm and, on the basis of the assay results, the use of chemotherapy in the adjuvant setting. METHODS: UPMC CancerCenter retrospectively reviewed patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)Neu-negative disease with zero to three positive nodes navigated in the Via Pathways decision support portal during a 12-month period. The breast algorithm prompted input of the assay recurrence score (RS) and then recommended hormonal therapy alone (HT) for low RS, or chemotherapy followed by HT for high RS. The patient's RS was correlated with the treatment decision. RESULTS: During this time period, 643 patients had ER-positive, HER2Neu-negative disease with zero to three positive nodes. Of those, 596 (92.7%) had diagnostic testing to determine chemotherapy plus HT versus HT alone, and 47 had chemotherapy followed by HT without an RS. For node-negative patients classified with low or high RS, pathway treatment adherence rates were 99.7% and 96.6%, respectively; node-positive patients had 95.7% and 87.5% adherence rates, respectively. CONCLUSION: This analysis demonstrates the use of a clinical pathway to measure the adoption of a diagnostic test, the Oncotype DX breast assay, and the use of the appropriate therapy on the basis of the RS. As more diagnostics are established to aid in the personalized treatment of diseases, pathways may be important in maintaining clinician awareness of the appropriate disease presentations where these tests should be used, measuring usage of these tests, and tracking the treatment decisions on the basis of test results.

Predictive and prognostic value of the 21-gene recurrence score in hormone receptor-positive, node-positive breast cancer.

The addition of adjuvant chemotherapy to hormonal therapy is recommended for patients with estrogen receptor-positive (ER+), node-positive (N+) early breast cancer (EBC). Some of these patients, however, are not likely to benefit from treatment and may, therefore, be overtreated while also incurring unnecessary treatment-related adverse events and health care costs. The 21-gene Recurrence Score assay has been clinically validated and recommended for use in patients with ER+, node-negative (N0) EBC to assess the 10-year risk of distant disease recurrence and predict the likelihood of response to adjuvant chemotherapy. A growing body of evidence from several large phase III clinical trials reports similar findings in patients with ER+, N+ EBC. A systematic review of published literature from key clinical trials that have used the 21-gene breast cancer assay in patients with ER+, N+ EBC was performed. The Recurrence Score has been shown to be an independent predictor of disease-free survival, overall survival, and distant recurrence-free interval in patients with ER+, N+ EBC. Outcomes from decision impact and health economics studies further indicate that the Recurrence Score affects physician treatment recommendations equally in patients with N+ or N0 disease. It also indicates that a reduction in Recurrence Score-directed chemotherapy is cost-effective. There is a large body of evidence to support the use of the 21-gene assay Recurrence Score in patients with N+ EBC. Use of this assay could help guide treatment decisions for patients who are most likely to receive benefit from chemotherapy.

The use of adjuvant bisphophonates in the treatment of early-stage breast cancer.

Adjuvant treatment of breast cancer has resulted in significant improvement in breast cancer-related outcomes. In addition to chemotherapy and endocrine therapy, the bone-protective agents known as bisphosphonates have been extensively investigated for their putative antitumor effect. Backed by strong preclinical data from in vitro and in vivo models, several randomized clinical trials have evaluated the role of bisphosphonates in an adjuvant setting. The recent NSABP B-34 (National Surgical Adjuvant Breast and Bowel Project protocol B-34) and AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) studies found no disease-free survival benefit with clodronate and zoledronate, respectively, whereas the ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group trial 12) study found improvement in disease-free survival with zoledronate. Data from these trials suggested a beneficial effect of bisphosphonates in older, postmenopausal women and in premenopausal women treated with ovarian suppression. Given the acceptable toxicity profile of bisphosphonates, these agents could be a useful adjunct to adjuvant chemotherapy or endocrine treatment for early-stage breast cancer in a carefully selected subset of patients. This review aims to critically synthesize the results of clinical trials of adjuvant bisphosphonates in early-stage breast cancer, and to provide guidelines for the use of these agents in early-stage breast cancer.

Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial.

BACKGROUND: We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment, and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients. METHODS: For this open-label, randomised phase 3 trial we recruited women aged 18 years or older with an ECOG performance status of 0 or 1 with operable HER2-positive breast cancer. Each received four cycles of standard doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously on day 1 every 3 weeks followed by four cycles of weekly paclitaxel (80 mg/m(2)) intravenously on days 1, 8, and 15, every 4 weeks. Concurrently with weekly paclitaxel, patients received either trastuzumab (4 mg/kg load, then 2 mg/kg intravenously) weekly until surgery, lapatinib (1250 mg orally) daily until surgery, or weekly trastuzumab plus lapatinib (750 mg orally) daily until surgery. After surgery, all patients received trastuzumab to complete 52 weeks of HER2-targeted therapy. Randomisation (ratio 1:1:1) was done centrally with stratification by clinical tumour size, clinical nodal status, hormone-receptor status, and age. The primary endpoint was the pathological complete response in the breast, and analysis was performed on an intention-to-treat population. FINDINGS: Patient accrual started on July 16, 2007, and was completed on June 30, 2011; 529 women were enrolled in the trial. 519 patients had their pathological response determined. Breast pathological complete response was noted in 93 (52·5%, 95% CI 44·9-59·5) of 177 patients in the trastuzumab group, 91 (53·2%, 45·4-60·3) of 171 patients in the lapatinib group (p=0·9852); and 106 (62·0%, 54·3-68·8) of 171 patients in the combination group (p=0·095). The most common grade 3 and 4 toxic effects were neutropenia (29 [16%] patients in the trastuzumab group [grade 4 in five patients (3%), 28 [16%] in the lapatinib group [grade 4 in eight patients (5%)], and 29 [17%] in the combination group [grade 4 in nine patients (5%)]) and grade 3 diarrhoea (four [2%] patients in the trastuzumab group, 35 [20%] in the lapatinib group, and 46 [27%] in the combination group; p<0·0001). Symptomatic congestive heart failure defined as New York Heart Association Class III or IV events occurred in seven (4%) patients in the trastuzumab group, seven (4%) in the lapatinib group, and one (<1%) in the combination group; p=0·185). INTERPRETATION: Substitution of lapatinib for trastuzumab in combination with chemotherapy resulted in similar high percentages of pathological complete response. Combined HER2-targeted therapy produced a numerically but insignificantly higher pathological complete response percentage than single-agent HER2-directed therapy; these findings are consistent with results from other studies. Trials are being undertaken to further assess these findings in the adjuvant setting.