Daniel J. Booser

Significantly Higher Pathologic Complete Remission Rate After Neoadjuvant Therapy With Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy: Results of a Randomized Trial in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer

PURPOSE The objective of this study was to determine whether the addition of trastuzumab to chemotherapy in the neoadjuvant setting could increase pathologic complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2) -positive disease. PATIENTS AND METHODS Forty-two patients with HER2-positive disease with operable breast cancer were randomly assigned to either four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. The primary objective was to demonstrate a 20% improvement in pCR (assumed 21% to 41%) with the addition of trastuzumab to chemotherapy. The planned sample size was 164 patients. RESULTS Prognostic factors were similar in the two groups. After 34 patients had completed therapy, the trials Data Monitoring Committee stopped the trial because of superiority of trastuzumab plus chemotherapy. pCR rates were 25% and 66.7% for chemotherapy (n = 16) and trastuzumab plus chemotherapy (n = 18), respectively (P = .02). The decision was based on the calculation that, if study continued to 164 patients, there was a 95% probability that trastuzumab plus chemotherapy would be superior. Of the 42 randomized patients, 26% in the chemotherapy arm achieved pCR compared with 65.2% in the trastuzumab plus chemotherapy arm (P = .016). The safety of this approach is not established, although no clinical congestive heart failure was observed. A more than 10% decrease in the cardiac ejection fraction was observed in five and seven patients in the chemotherapy and trastuzumab plus chemotherapy arms, respectively. CONCLUSION Despite the small sample size, these data indicate that adding trastuzumab to chemotherapy, as used in this trial, significantly increased pCR without clinical congestive heart failure.

Pharmacogenomic Predictor of Sensitivity to Preoperative Chemotherapy With Paclitaxel and Fluorouracil, Doxorubicin, and Cyclophosphamide in Breast Cancer

PURPOSE We developed a multigene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy and assessed its predictive accuracy on independent cases. PATIENTS AND METHODS One hundred thirty-three patients with stage I-III breast cancer were included. Pretreatment gene expression profiling was performed with oligonecleotide microarrays on fine-needle aspiration specimens. We developed predictors of pCR from 82 cases and assessed accuracy on 51 independent cases. RESULTS Overall pCR rate was 26% in both cohorts. In the training set, 56 probes were identified as differentially expressed between pCR versus residual disease, at a false discovery rate of 1%. We examined the performance of 780 distinct classifiers (set of genes + prediction algorithm) in full cross-validation. Many predictors performed equally well. A nominally best 30-probe set Diagonal Linear Discriminant Analysis classifier was selected for independent validation. It showed significantly higher sensitivity (92% v 61%) than a clinical predictor including age, grade, and estrogen receptor status. The negative predictive value (96% v 86%) and area under the curve (0.877 v 0.811) were nominally better but not statistically significant. The combination of genomic and clinical information yielded a predictor not significantly different from the genomic predictor alone. In 31 samples, RNA was hybridized in replicate with resulting predictions that were 97% concordant. CONCLUSION A 30-probe set pharmacogenomic predictor predicted pCR to T/FAC chemotherapy with high sensitivity and negative predictive value. This test correctly identified all but one of the patients who achieved pCR (12 of 13 patients) and all but one of those who were predicted to have residual disease had residual cancer (27 of 28 patients).

Phase II Study of Weekly Docetaxel and Trastuzumab for Patients With HER-2–Overexpressing Metastatic Breast Cancer

PURPOSE To evaluate the safety and efficacy of weekly docetaxel plus trastuzumab in women with HER-2-overexpressing metastatic breast cancer. Efficacy was correlated with serum HER-2 extracellular domain (ECD) levels. PATIENTS AND METHODS Thirty women with metastatic breast cancer were treated with weekly docetaxel and trastuzumab as first- or second-line therapy. Both docetaxel 35 mg/m(2)/wk and trastuzumab 2 mg/kg/wk were delivered in 4-week cycles consisting of three weekly treatments followed by 1 week of rest. A loading dose of trastuzumab 4 mg/kg was administered 1 day before the start of the first cycle. RESULTS The median delivered dose-intensity of docetaxel was 24 mg/m(2)/wk (range, 18 to 27 mg/m(2)/wk). The intent-to-treat overall response rate (ORR) was 63% (95% confidence interval [CI], 44% to 80%). The ORR in patients whose tumors were HER-2-positive by fluorescence in situ hybridization was 67% (16 of 24 patients; 95% CI, 45% to 84%). In patients with elevated serum HER-2 ECD at baseline, the ORR was 76% (95% CI, 53% to 92%), compared with 33% (95% CI, 7% to 70%) in patients with low HER-2 ECD levels (P =.04). Variations in HER-2 ECD concentrations during treatment correlated with response to treatment. Median time to progression was 9 months. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and excessive tearing became more common with repetitive dosing. CONCLUSION Weekly docetaxel and trastuzumab is an active combination for treating patients with HER-2-overexpressing metastatic breast cancer. Serum HER-2 ECD testing may be a promising method for monitoring patients on trastuzumab-based therapy.

Weekly Paclitaxel Improves Pathologic Complete Remission in Operable Breast Cancer When Compared With Paclitaxel Once Every 3 Weeks

PURPOSE To determine the impact a change in schedule of paclitaxel administration from once every 3 weeks to frequent administration would have on the pathologic complete response (pCR) rate in the breast and lymph nodes for patients with invasive breast cancer treated with primary systemic chemotherapy (PST). PATIENTS AND METHODS Patients with clinical stage I-IIIA breast cancer were randomly assigned to receive PST of paclitaxel doses administered either weekly (for a total of 12 doses of paclitaxel) or once every 3 weeks (four cycles), followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses every 3 weeks. Two different doses of paclitaxel were used based on lymph node status defined by ultrasound and fine needle aspiration. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after completion of all chemotherapy. RESULTS A total of 258 patients were randomly assigned to receive doses of paclitaxel administered either weekly or once every 3 weeks, followed by FAC. Of these 258 patients, 110 patients had histologic lymph node involvement and 148 patients had clinical N0 disease. Weekly paclitaxel followed by FAC was administered to 127 patients and once-every-3-weeks paclitaxel followed by FAC was administered to 131 patients. Clinical response to treatment was similar between groups (P = .25). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with once-every-3-weeks paclitaxel (15.7%; P = .02), with improved breast conservation rates (P = .05). CONCLUSION The change in schedule of paclitaxel from once every 3 weeks to a more frequent administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes.

A Genomic Predictor of Response and Survival Following Taxane-Anthracycline Chemotherapy for Invasive Breast Cancer

CONTEXT Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies. OBJECTIVE To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer. DESIGN, SETTING, AND PATIENTS Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens (then endocrine therapy if estrogen receptor [ER]-positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response. MAIN OUTCOME MEASURES Distant relapse-free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years). RESULTS Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy. CONCLUSION A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.

Management of Breast Cancer During Pregnancy Using a Standardized Protocol

PURPOSE No standardized therapeutic interventions have been reported for patients diagnosed with breast cancer during pregnancy. Of the potential interventions, none have been prospectively evaluated for treatment efficacy in the mother or safety for the fetus. We present our experience with the use of combination chemotherapy for breast cancer during pregnancy. PATIENTS AND METHODS During the past 8 years, 24 pregnant patients with primary or recurrent cancer of the breast were managed by outpatient chemotherapy, surgery, or surgery plus radiation therapy, as clinically indicated. The chemotherapy included fluorouracil (1,000 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2), administered every 3 to 4 weeks after the first trimester of pregnancy. Care was provided by medical oncologists, breast surgeons, and perinatal obstetricians. RESULTS Modified radical mastectomy was performed in 18 of the 22 patients, and two patients were treated with segmental mastectomy with postpartum radiation therapy. This group included patients in all trimesters of pregnancy. The patients received a median of four cycles of combination chemotherapy during pregnancy. No antepartum complications temporally attributable to systemic therapy were noted. The mean gestational age at delivery was 38 weeks. Apgar scores, birthweights, and immediate postpartum health were reported to be normal for all of the children. CONCLUSION Breast cancer can be treated with chemotherapy during the second and third trimesters of pregnancy with minimal complications of labor and delivery.

Residual Risk of Breast Cancer Recurrence 5 Years After Adjuvant Therapy

There is limited prognostic information to identify breast cancer patients who are at risk for late recurrences after adjuvant or neoadjuvant systemic therapy (AST). We evaluated the residual risk of recurrence and prognostic factors of 2838 patients with stage I-III breast cancer who were treated with AST between January 1, 1985, and November 1, 2001, and remained disease free for 5 years. Residual recurrence-free survival was estimated from the landmark of 5 years after AST to date of first recurrence or last follow-up using the Kaplan-Meier method. The log-rank test (two-sided) was used to compare groups. Residual recurrence-free survival rates at 5 and 10 years were 89% and 80%, respectively, and 216 patients developed a recurrence event. The 5-year residual risks of recurrence for patients with stage I, II, and III cancers were 7% (95% confidence interval [CI] = 3% to 15%), 11% (95% CI = 9% to 13%), and 13% (95% CI = 10% to 17%), respectively (P = .02). In multivariable analysis, stage, grade, hormone receptor status, and endocrine therapy were associated with late recurrences. Breast cancer patients have a substantial residual risk of recurrence, and selected tumor characteristics are associated with late recurrences.

Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma

The primary objective of this study was to determine whether addition of the selective P‐glycoprotein (P‐gp) inhibitor tariquidar (XR9576) to chemotherapy could induce an objective tumor response in patients who previously were resistant to the same agents. The secondary objectives were to evaluate P‐gp expression by immunohistochemistry (IHC), to determine functional activity of the P‐gp transporter before and after administration of tariquidar with serial technetium‐99m (99mTc)‐sestamibi scans, and to correlate those parameters with clinical response.

Anthracycline Antibiotics in Cancer Therapy: Focus on Drug Resistance

Summary30 years ago an anthracycline antibiotic was shown to have antineoplastic activity. This led to the development of well over 1000 analogues with a vast spectrum of biochemical characteristics. Many biological actions have been described. The original anthracyclines are active against many types of cancer and are an integral part of several curative combinations. They are ineffective against other tumours. Although some analogues show an altered spectrum of activity or an improved therapeutic index relative to the older agents, it is not clear that cardiotoxicity can be totally avoided with these agents.Primary and secondary resistance to anthracyclines remain major clinical problems. Pharmacokinetic studies have been of limited help in explaining this. Overexpression of a surface-membrane permeability glycoprotein (Pgp) was identified in ovarian cancer of patients who had clinical multidrug resistance in 1985. This led the way for the discovery of a number of resistance mechanisms in vitro. Some of these have been found in more than 1 type of cell line, and more than 1 mechanism may exist in a single cell. Additional resistance proteins have been identified, qualitative and quantitative alterations of topoisomerase II have been described, and some mechanisms in other systems have not yet been identified. Some of these may prove to be important in clinical drug resistance.Drugs such as calcium antagonists and cyclosporin, studied initially for their ability to block the Pgp pump, appear to be heterogeneous in this capacity and may have additional sites of action. It will be critical for clinical studies to define the precise resistance mechanism(s) that must be reversed. To date this has been difficult, even in trials ostensibly dealing with the original Pgp.Liposomes can potentially alter toxicity and target drug delivery to specific sites. In addition, they may permit the use of lipophilic drugs that would otherwise be difficult to administer systemically. Resistant tumours may be sensitive to anthracyclines delivered by liposomes.To reduce cardiac toxicity, administering doxorubicin (adriamycin) by slow infusion through a central-venous line should be considered whenever feasible. Monitoring of cardiac ejection fraction and the use of endomyocardial biopsy will permit patients to be treated safely after they reach the dose threshold at which heart failure begins to be a potential risk.A number of structurally modified anthracyclines with the potential advantages of decreased cardiotoxicity and avoidance of multidrug resistance mechanisms are entering clinical trials. Meanwhile, the vast weight of clinical experience leaves doxorubicin as a well tolerated and effective choicc for most potentially anthracycline-sensitive tumours.

Phase I/II Study of Trastuzumab in Combination With Everolimus (RAD001) in Patients With HER2-Overexpressing Metastatic Breast Cancer Who Progressed on Trastuzumab-Based Therapy

PURPOSE Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy. PATIENTS AND METHODS This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus. RESULTS Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss. CONCLUSION Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.