Chau T. Dang

Adjuvant Paclitaxel and Trastuzumab for Node-Negative, HER2-Positive Breast Cancer

BACKGROUND No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)-positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab. METHODS We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease. RESULTS The median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contralateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption. CONCLUSIONS Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451.).

Troponin I and C-Reactive Protein Are Commonly Detected in Patients with Breast Cancer Treated with Dose-Dense Chemotherapy Incorporating Trastuzumab and Lapatinib

Purpose: There are no validated methods of early detection of cardiotoxicity from trastuzumab (T) following anthracycline-based chemotherapy. Currently changes in left ventricular ejection fraction (LVEF) are assessed but this approach has limited sensitivity and specificity. Within a prospective feasibility study of dose-dense (dd) doxorubicin and cyclophosphamide (AC) → weekly paclitaxel (P) with T and lapatinib (L), we included a preplanned analysis of correlative cardiac Troponin I (cTnI) and C-reactive protein (CRP) as early biomarkers of cardiotoxicity. Experimental Design: As previously described, patients received ddACx 4→PTL→TL. LVEF was assessed at months 0, 2, 6, 9, and 18 and cTnI and CRP measured every 2 weeks during chemotherapy then at months 6, 9, and 18. These biomarkers were correlated with changes in LVEF. Results: Ninety-five patients enrolled. Overall, 3 (3%) patients withdrew during AC and 41 (43%) withdrew during PTL→TL, mostly due to diarrhea. Median LVEF was 68% (baseline), 69% (month 2), 65% (month 6), 65% (month 9), and 65% (month 18). The majority (67%) had a detectable cTnI during the study. The proportion of detectable cTnIs increased over time; 4% at baseline, 11% at month 2, and 50% at month 3. The timing of these detectable cTnIs preceded maximum-recorded decline in LVEF. However, overall, maximum cTnI levels did not correlate with LVEF declines. A detectable CRP was seen in 74/95 (78%) but did not correlate with LVEF declines. Conclusion: In patients receiving ddAC→PTL, cTnIs are commonly detected. These elevations may precede changes in LVEF but, as assessed in this trial, do not predict CHF. Clin Cancer Res; 17(10); 3490–9. ©2011 AACR.

A Phase II Trial of Erlotinib in Combination with Bevacizumab in Patients with Metastatic Breast Cancer

Purpose: To evaluate the efficacy and toxicity of erlotinib plus bevacizumab in patients with metastatic breast cancer (MBC), targeting the epidermal growth factor receptor (EGFR/HER1) and the vascular endothelial growth factor (VEGF) pathway. Experimental Design: Thirty-eight patients with MBC were enrolled and treated at two institutions with erlotinib, a small molecule EGFR tyrosine kinase inhibitor (150 mg p.o. daily) plus bevacizumab, an anti-VEGF antibody (15 mg/kg i.v. every 3 weeks). Patients had one to two prior chemotherapy regimens for metastatic disease. The primary end point was response rate by Response Evaluation Criteria in Solid Tumors criteria using a Simon 2-stage design. Secondary end points included toxicity, time to progression, response duration, and stabilization of disease of ≥26 weeks. Correlative studies were done on tumor tissue, including EGFR expression and mutation analysis. Results: One patient achieved a partial response for 52+ months. Fifteen patients had stable disease at first evaluation at 9 weeks; 4 of these patients had stable disease beyond 26 weeks. Median time to progression was 11 weeks (95% confidence interval, 8-18 weeks). Diarrhea of any grade was observed in 84% of patients (grade 3 in 3%); 76% experienced grade 1 or 2 skin rash, and 18% developed hypertension (grade 3 in 11%). The level of EGFR expression was not predictive of response to therapy. Conclusions: The combination of erlotinib and bevacizumab was well-tolerated but had limited activity in unselected patients with previously treated MBC. Biomarkers are needed to identify those MBC patients likely to respond to anti-EGFR/HER1 plus anti-VEGF therapy.

Phase II Study of Celecoxib and Trastuzumab in Metastatic Breast Cancer Patients Who Have Progressed after Prior Trastuzumab-Based Treatments

Purpose: Preclinical studies demonstrate a link between overexpression of HER-2/neu and cyclooxygenase-2 (COX-2) activity. To explore the possibility that COX-2 is a therapeutic target, we conducted a phase II study of celecoxib, a selective COX-2 inhibitor, and trastuzumab in patients with HER-2/neu-overexpressing metastatic breast cancer that had progressed while receiving trastuzumab. Experimental Design: Eligible patients had bi-dimensionally measurable or evaluable HER-2/neu-overexpressing metastatic breast cancer. HER-2/neu overexpression, defined as 2+ or 3+ by the HercepTest, was required. Patients had to have progressed despite prior trastuzumab-based therapy. Treatment consisted of celecoxib (400 mg twice daily) and trastuzumab. Results: Twelve patients were enrolled (42% status post 1 regimen for metastatic disease 58% status post > 2 prior regimens (range of 2–6). Eleven patients were evaluable. There were no responses. Median duration of treatment was 9 weeks. One patient had stable disease at 3 months but progressed at 6 months. A second patient stopped treatment at 3 months because of unresolved grade 2 rash, felt to be related to celecoxib. Toxicities were generally grade 1 or 2. One patient (8%) experienced grade 3 toxicity (abdominal pain). Conclusions: Celecoxib combined with trastuzumab is well tolerated. However, this combination in patients with HER2/neu-overexpressing, trastuzumab-refractory disease, was not active.

Increased Levels of Urinary PGE-M, a Biomarker of Inflammation, Occur in Association with Obesity, Aging, and Lung Metastases in Patients with Breast Cancer

Elevated levels of COX-derived prostaglandin E2 (PGE2) occur in inflamed tissues. To evaluate the potential links between inflammation and breast cancer, levels of urinary prostaglandin E metabolite (PGE-M), a stable end metabolite of PGE2, were quantified. We enrolled 400 patients with breast cancer: controls with early breast cancer (n = 200), lung metastases (n = 100), and metastases to other sites (n = 100). Patients completed a questionnaire, provided urine, and had measurements of height and weight. Urinary PGE-M was quantified by mass spectrometry. Ever smokers with lung metastasis who had not been exposed to nonsteroidal anti-inflammatory drugs (NSAIDs) had the highest PGE-M levels. PGE-M levels were increased in association with elevated body mass index (BMI; P < 0.001), aging (P < 0.001), pack-year smoking history (P = 0.02), lung metastases (P = 0.02), and recent cytotoxic chemotherapy (P = 0.03). Conversely, use of NSAIDs, prototypic inhibitors of COX activity, was associated with reduced PGE-M levels (P < 0.001). On the basis of the current findings, PGE-M is likely to be a useful biomarker for the selection of high-risk subgroups to determine the use of interventions that aim to reduce inflammation and possibly the development and progression of breast cancer, especially in overweight and obese women. Cancer Prev Res; 6(5); 428–36. ©2013 AACR.

Phase II Study of Feasibility of Dose-Dense FEC Followed by Alternating Weekly Taxanes in High-Risk, Four or More Node-Positive Breast Cancer

Purpose: To develop a potentially superior adjuvant chemotherapy regimen, we conducted a pilot study of dose-dense 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by weekly alternating taxanes. The primary objective was to determine the feasibility of the regimen; the secondary objective was to estimate the disease-free and overall survival. Experimental Design: Patients with ≥4 node-positive breast cancer were studied. Treatment consisted of FEC at 500/100/500 mg/m2, respectively, ×6 at two-week intervals with granulocyte colony-stimulating factor, followed by weekly paclitaxel (80 mg/m2) alternating with docetaxel (35 mg/m2) ×18. Results: Between November 2001 and January 2003, 44 patients were enrolled. Median age was 46 years (range, 26–63 years), median number of positive nodes was 9 (range, 4–32), and median tumor size was 2.5 cm (range, 0.6–11.0 cm). Because of unexpected toxicities, the study was stopped when 17 (39%) had fully completed all of the planned treatment. Two of 17 (12%) developed grade 4 pericardial/grade 3 bilateral pleural effusions at treatment completion; both required pericardial window. The remaining patients were treated with taxanes using one of several standard dose and schedule combinations. Furthermore, 4 of 44 (9%) developed pneumonitis attributed to the FEC regimen. Hospital admissions were required for 12 of 44 (27%); 3 of 44 (7%) required blood transfusions. There were no treatment related deaths. Median disease-free and overall survival will not be estimatable because of early closure of study. Conclusion: FEC ×6 at 2-week intervals followed by 18 weeks of alternating taxanes is not feasible at the doses tested. Other strategies are needed to improve adjuvant systemic chemotherapy.

Abstract S1-04: A phase II study of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC)

Background: Four large randomized phase III trials have reported significant improvements in disease-free (DFS) and overall survival for H administered with adjuvant polychemotherapy for HER2-positive high-risk BC. With the success of HER2-targeting, limiting chemotherapy is both reasonable and feasible, particularly for smaller, node-negative tumors. However data are limited. Methods: APT is a single arm three-stage, multicenter, phase II study of TH. Patients (pts) with HER2-positive BC (IHC 3 + and/or FISH amplified at > 2.0) with negative nodes (a single axillary lymph node micrometastasis was allowed) and tumor size Results: 410 pts were enrolled from September 2007 to September 2010 and 406 began protocol therapy. The median age was 55 (range 24-85 years). Sixty-three percent had ER+ tumors. Three percent of tumors were T1mi; T1a; 20% T1b; 41% T1c, and 9% T2 ≤ 3cm. Six pts had a nodal micrometastasis. 356 pts (88%) completed all 52 wks of therapy, with 24 and 6 pts discontinuing due to protocol-specified or other toxicities, respectively. 358 (89%) completed all 12 weeks of combined TH therapy. The most common grade 3/4 toxicities included: neuropathy (4%), neutropenia (4%), transaminitis (3%), leukopenia (2%), fatigue (2%), and hypersensitivity reactions (2%). Reversible symptomatic CHF (grade 3 left ventricular systolic dysfunction) occurred in 2 patients (0.5%). Because of the limited number of events, the Data Safety Monitoring Board approved release of study results with 1316 PYFU and a median follow-up of 3.2 years. A total of 8 DFS events have been observed: 2 pts with metastatic disease, 2 with ipsilateral axillary recurrences, 3 with new contralateral BC (all HER2-), and 1 patient who died after diagnosis of primary ovarian cancer. Conclusion: This represents the first report of TH as adjuvant therapy for node-negative HER2-positive BC. The regimen appears well tolerated and few recurrences have been observed in the study population to date. An updated analysis of efficacy, including estimates of 3-year DFS, will be presented in December when a total of 1520 PYFU in this cohort is anticipated. Based on these early data, the TH regimen may be an acceptable treatment approach for low risk HER2-positive breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-04.

Dose-Dense Adjuvant Doxorubicin and Cyclophosphamide Is Not Associated With Frequent Short-Term Changes in Left Ventricular Ejection Fraction

PURPOSE Doxorubicin and cyclophosphamide (AC) every 3 weeks has been associated with frequent asymptomatic declines in left ventricular ejection fraction (LVEF). Dose-dense (dd) AC followed by paclitaxel (P) is superior to the same regimen given every third week. Herein, we report the early cardiac safety of three sequential studies of ddAC alone or with bevacizumab (B). PATIENTS AND METHODS Patients with HER2-positive breast cancer were treated on two trials: ddAC followed by P and trastuzumab (T) and ddAC followed by PT and lapatinib. Patients with HER2-normal breast cancer were treated with B and ddAC followed by B and nanoparticle albumin-bound P. Prospective LVEF measurement by multigated radionuclide angiography scan before and after every 2 week AC for 4 cycles and at month 6 from all three trials were aggregated to determine the early risks of cardiac dysfunction. RESULTS From January 2005 to May 2008, 245 patients were enrolled. The median age was 47 years (range, 27 to 75 years). Median LVEF pre-ddAC was 68% (range, 52% to 82%). LVEF post-ddAC was available in 241 patients (98%) and the median was unchanged at 68% (range, 47% to 81%). Per protocol no patients were ineligible for subsequent targeted biologic therapy based on LVEF decline post-ddAC. In addition, LVEF was available in 222 patients (92%) at 6 months, at which time the median LVEF was similar at 65% (range, 24% to 80%). Within 6 months of initiating chemotherapy, three patients (1.2%; 95% CI, 0.25% to 3.54%) developed CHF, all of whom received T. CONCLUSION Dose-dense AC with or without concurrent bevacizumab is not associated with frequent acute or short-term declines in LVEF.

Cardiac Surveillance Guidelines for Trastuzumab-Containing Therapy in Early-Stage Breast Cancer: Getting to the Heart of the Matter

Trastuzumab-containing regimens for breast cancer have significantly improved survival both in the early-stage and metastatic settings.1-8 Nevertheless, given the early signals of cardiotoxicity, a prevailing concern exists regarding the risk of cardiotoxicity, defined as a decline in left ventricular ejection fraction (LVEF) both asymptomatic and symptomatic. This concern that LVEF decline would be an early and actionable surrogate for subsequent development of congestive heart failure (CHF) led to the design and implementation of specific eligibility criteria and LVEF surveillance guidelines for the pivotal randomized adjuvant trials. These guidelines were subsequently adopted as the standard of care. However, it is increasingly unclear whether these specific recommendations are justified for all patients. Resolution of this matter is critical for our community because adherence to these guidelines was recently proposed as a quality metric.9 This issue raises the general question of the level of evidence needed to accept a toxicity screening schedule as a quality indicator. If following these guidelines is not associated with improved outcomes, then adherence to them as a quality metric should be challenged. Cardiotoxicity screening can serve to illuminate this issue. Here, we review the historical events that led to the development of the current guidelines and highlight critical knowledge gaps with regard to the benefits of screening and intervention.

Feasibility and Cardiac Safety of Trastuzumab Emtansine After Anthracycline-Based Chemotherapy As (neo)Adjuvant Therapy for Human Epidermal Growth Factor Receptor 2–Positive Early-Stage Breast Cancer

PURPOSE Trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprising the cytotoxic agent DM1, a stable linker, and trastuzumab, has demonstrated substantial activity in human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer, raising interest in evaluating the feasibility and cardiac safety of T-DM1 in early-stage breast cancer (EBC). PATIENTS AND METHODS Patients (N = 153) with HER2-positive EBC and prechemotherapy left ventricular ejection fraction (LVEF) ≥ 55% received (neo)adjuvant doxorubicin plus cyclophosphamide or fluorouracil plus epirubicin plus cyclophosphamide followed by T-DM1 for four cycles. Patients could then receive three to four cycles of optional docetaxel with or without trastuzumab. T-DM1 was then resumed with optional radiotherapy (sequential or concurrent) for 1 year (planned) of HER2-directed therapy. The coprimary end points were rate of prespecified cardiac events and safety. RESULTS Median follow-up was 24.6 months. No prespecified cardiac events or symptomatic congestive heart failures were reported. Four patients (2.7%) had asymptomatic LVEF declines (≥ 10 percentage points from baseline to LVEF < 50%), leading to T-DM1 discontinuation in one patient. Of 148 patients who received ≥ one cycle of T-DM1, 82.4% completed the planned 1-year duration of HER2-directed therapy. During T-DM1 treatment, 38.5% and 2.7% of patients experienced grade 3 and 4 adverse events, respectively. Approximately 95% of patients receiving T-DM1 plus radiotherapy completed ≥ 95% of the planned radiation dose with delay ≤ 5 days. CONCLUSION Use of T-DM1 for approximately 1 year after anthracycline-based chemotherapy was feasible and generally well tolerated by patients with HER2-positive EBC, providing support for phase III trials of T-DM1 in this setting.