Rita S. Mehta

Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer

BACKGROUND Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response. METHODS We randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and 8) for four cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy. RESULTS The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P=0.69). Both capecitabine and gemcitabine were associated with increased toxic effects--specifically, the hand-foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P=0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor-positive and hormone-receptor-negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand-foot syndrome, and mucositis. CONCLUSIONS The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.).

Predicting response to breast cancer neoadjuvant chemotherapy using diffuse optical spectroscopy

Diffuse optical spectroscopy (DOS) and imaging are emerging diagnostic techniques that quantitatively measure the concentration of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctO2Hb), water (ctH2O), and lipid in cm-thick tissues. In early-stage clinical studies, diffuse optical imaging and DOS have been used to characterize breast tumor biochemical composition and monitor therapeutic response in stage II/III neoadjuvant chemotherapy patients. We investigated whether DOS measurements obtained before and 1 week into a 3-month adriamycin/cytoxan neoadjuvant chemotherapy regimen can predict final, postsurgical pathological response. Baseline DOS measurements of 11 patients before therapy revealed significant increases in tumor ctHHb, ctO2Hb, ctH2O, and spectral scattering slope, and decreases in bulk lipids, relative to normal breast tissue. Tumor concentrations of ctHHb, ctO2Hb, and ctH2O dropped 27 ± 15%, 33 ± 7%, and 11 ± 15%, respectively, within 1 week (6.5 ± 1.4 days) of the first treatment for pathology-confirmed responders (n = 6), whereas nonresponders (n = 5) and normal side controls showed no significant changes in these parameters. The best single predictor of therapeutic response 1 week posttreatment was ctHHb (83% sensitivity, 100% specificity), while discrimination analysis based on combined ctHHb and ctH2O changes classified responders vs. nonresponders with 100% sensitivity and specificity. In addition, the pretreatment tumor-to-normal ctO2Hb ratio was significantly higher in responders (2.82 ± 0.44) vs. nonresponders (1.82 ± 0.49). These results highlight DOS sensitivity to tumor cellular metabolism and biochemical composition and demonstrate its potential for predicting and monitoring an individuals response to treatment.

Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer

BACKGROUND The aromatase inhibitor anastrozole inhibits estrogen synthesis. Fulvestrant binds and accelerates degradation of estrogen receptors. We hypothesized that these two agents in combination might be more effective than anastrozole alone in patients with hormone-receptor (HR)-positive metastatic breast cancer. METHODS Postmenopausal women with previously untreated metastatic disease were randomly assigned, in a 1:1 ratio, to receive either 1 mg of anastrozole orally every day (group 1), with crossover to fulvestrant alone strongly encouraged if the disease progressed, or anastrozole and fulvestrant in combination (group 2). Patients were stratified according to prior or no prior receipt of adjuvant tamoxifen therapy. Fulvestrant was administered intramuscularly at a dose of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter. The primary end point was progression-free survival, with overall survival designated as a prespecified secondary outcome. RESULTS The median progression-free survival was 13.5 months in group 1 and 15.0 months in group 2 (hazard ratio for progression or death with combination therapy, 0.80; 95% confidence interval [CI], 0.68 to 0.94; P=0.007 by the log-rank test). The combination therapy was generally more effective than anastrozole alone in all subgroups, with no significant interactions. Overall survival was also longer with combination therapy (median, 41.3 months in group 1 and 47.7 months in group 2; hazard ratio for death, 0.81; 95% CI, 0.65 to 1.00; P=0.05 by the log-rank test), despite the fact that 41% of the patients in group 1 crossed over to fulvestrant after progression. Three deaths that were possibly associated with treatment occurred in group 2. The rates of grade 3 to 5 toxic effects did not differ significantly between the two groups. CONCLUSIONS The combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant that was below the current standard. (Funded by the National Cancer Institute and AstraZeneca; SWOG ClinicalTrials.gov number, NCT00075764.).

MRI evaluation of pathologically complete response and residual tumors in breast cancer after neoadjuvant chemotherapy

This study investigated the role of magnetic resonance imaging (MRI) in evaluation of pathologically complete response and residual tumors in patients who were receiving neoadjuvant chemotherapy (NAC) for both positive and negative HER‐2 breast cancer.

Diffuse Optical Monitoring of Blood Flow and Oxygenation in Human Breast Cancer During Early Stages of Neoadjuvant Chemotherapy

We combine diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) to noninvasively monitor early hemodynamic response to neoadjuvant chemotherapy in a breast cancer patient. The potential for early treatment monitoring is demonstrated. Within the first week of treatment (day 7) DOS revealed significant changes in tumor/normal contrast compared to pretreatment (day 0) tissue concentrations of deoxyhemoglobin (rctHHbT/N=69+/-21%), oxyhemoglobin (rctO2HbT/N=73+/-25%), total hemoglobin (rctTHbT/N=72+/-17%), and lipid concentration (rctLipidT/N=116+/-13%). Similarly, DCS found significant changes in tumor/normal blood flow contrast (rBFT/N=75+/-7% on day 7 with respect to day 0). Our observations suggest the combination of DCS and DOS enhances treatment monitoring compared to either technique alone. The hybrid approach also enables construction of indices reflecting tissue metabolic rate of oxygen, which may provide new insights about therapy mechanisms.

Predicting Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer by Using MR Imaging and Quantitative 1H MR Spectroscopy

PURPOSE To compare changes in the concentration of choline-containing compounds (tCho) and in tumor size at follow-up after neoadjuvant chemotherapy (NAC) between patients who achieved pathologic complete response (pCR) and those who did not (non-pCR). MATERIALS AND METHODS This study was approved by the institutional review board and was compliant with HIPAA; each patient gave informed consent. Thirty-five patients (mean age, 48 years +/- 11 [standard deviation]; range, 29-75 years) with breast cancer were included. Treatment included doxorubicin and cyclophosphamide followed by a taxane-based regimen. Changes in tCho and tumor size in pCR versus non-pCR groups were compared by using the two-way Mann-Whitney nonparametric test. Receiver operating characteristic (ROC) analysis was performed to differentiate between them and the area under the ROC curve (AUC) was compared. RESULTS In the pCR group, the tCho level change was greater compared with change in tumor size (P = .003 at first follow-up, P = .01 at second follow-up), but they were not significantly different in the non-pCR group. Changes in tumor size and tCho level at the first follow-up study were not significantly different between the pCR and non-pCR groups but reached significance at the second follow-up. In ROC analysis, the magnetic resonance (MR) imaging and MR spectroscopic parameters had AUCs of 0.65-0.68 at first follow-up; at second follow-up, AUC for change in tumor size was 0.9, AUC for change in tCho was 0.73. CONCLUSION Patients who show greater reduction in tCho compared with changes in tumor size are more likely to achieve pCR. The change in tumor size halfway through therapy was the most accurate predictor of pCR.

Endocrine Therapy for Hormone Receptor–Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline

PURPOSE To develop recommendations about endocrine therapy for women with hormone receptor (HR) -positive metastatic breast cancer (MBC). METHODS The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of evidence from 2008 through 2015 to create recommendations informed by that evidence. Outcomes of interest included sequencing of hormonal agents, hormonal agents compared with chemotherapy, targeted biologic therapy, and treatment of premenopausal women. This guideline puts forth recommendations for endocrine therapy as treatment for women with HR-positive MBC. RECOMMENDATIONS Sequential hormone therapy is the preferential treatment for most women with HR-positive MBC. Except in cases of immediately life-threatening disease, hormone therapy, alone or in combination, should be used as initial treatment. Patients whose tumors express any level of hormone receptors should be offered hormone therapy. Treatment recommendations should be based on type of adjuvant treatment, disease-free interval, and organ function. Tumor markers should not be the sole criteria for determining tumor progression; use of additional biomarkers remains experimental. Assessment of menopausal status is critical; ovarian suppression or ablation should be included in premenopausal women. For postmenopausal women, aromatase inhibitors (AIs) are the preferred first-line endocrine therapy, with or without the cyclin-dependent kinase inhibitor palbociclib. As second-line therapy, fulvestrant should be administered at 500 mg with a loading schedule and may be administered with palbociclib. The mammalian target of rapamycin inhibitor everolimus may be administered with exemestane to postmenopausal women with MBC whose disease progresses while receiving nonsteroidal AIs. Among patients with HR-positive, human epidermal growth factor receptor 2-positive MBC, human epidermal growth factor receptor 2-targeted therapy plus an AI can be effective for those who are not chemotherapy candidates.

Optical imaging of breast cancer oxyhemoglobin flare correlates with neoadjuvant chemotherapy response one day after starting treatment

Approximately 8–20% of breast cancer patients receiving neoadjuvant chemotherapy fail to achieve a measurable response and endure toxic side effects without benefit. Most clinical and imaging measures of response are obtained several weeks after the start of therapy. Here, we report that functional hemodynamic and metabolic information acquired using a noninvasive optical imaging method on the first day after neoadjuvant chemotherapy treatment can discriminate nonresponding from responding patients. Diffuse optical spectroscopic imaging was used to measure absolute concentrations of oxyhemoglobin, deoxyhemoglobin, water, and lipid in tumor and normal breast tissue of 24 tumors in 23 patients with untreated primary breast cancer. Measurements were made before chemotherapy, on day 1 after the first infusion, and frequently during the first week of therapy. Various multidrug, multicycle regimens were used to treat patients. Diffuse optical spectroscopic imaging measurements were compared with final postsurgical pathologic response. A statistically significant increase, or flare, in oxyhemoglobin was observed in partial responding (n = 11) and pathologic complete responding tumors (n = 8) on day 1, whereas nonresponders (n = 5) showed no flare and a subsequent decrease in oxyhemoglobin on day 1. Oxyhemoglobin flare on day 1 was adequate to discriminate nonresponding tumors from responding tumors. Very early measures of chemotherapy response are clinically convenient and offer the potential to alter treatment strategies, resulting in improved patient outcomes.

Baseline Tumor Oxygen Saturation Correlates with a Pathologic Complete Response in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy

Tissue hemoglobin oxygen saturation (i.e., oxygenation) is a functional imaging endpoint that can reveal variations in tissue hypoxia, which may be predictive of pathologic response in subjects undergoing neoadjuvant chemotherapy. In this study, we used diffuse optical spectroscopic imaging (DOSI) to measure concentrations of oxyhemoglobin (ctO(2)Hb), deoxy-hemoglobin (ctHHb), total Hb (ctTHb = ctO(2)Hb + ctHHb), and oxygen saturation (stO(2) = ctO(2)Hb/ctTHb) in tumor and contralateral normal tissue from 41 patients with locally advanced primary breast cancer. Measurements were acquired before the start of neoadjuvant chemotherapy. Optically derived parameters were analyzed separately and in combination with clinical biomarkers to evaluate correlations with pathologic response. Discriminant analysis was conducted to determine the ability of optical and clinical biomarkers to classify subjects into response groups. Twelve (28.6%) of 42 tumors achieved pathologic complete response (pCR) and 30 (71.4%) were non-pCR. Tumor measurements in pCR subjects had higher stO(2) levels (median 77.8%) than those in non-pCR individuals (median 72.3%, P = 0.01). There were no significant differences in baseline ctO(2)Hb, ctHHb, and ctTHb between response groups. An optimal tumor oxygenation threshold of stO(2) = 76.7% was determined for pCR versus non-pCR (sensitivity = 75.0%, specificity = 73.3%). Multivariate discriminant analysis combining estrogen receptor staining and stO(2) further improved the classification of pCR versus non-pCR (sensitivity = 100%, specificity = 85.7%). These results show that elevated baseline tumor stO(2) are correlated with a pCR. Noninvasive DOSI scans combined with histopathology subtyping may aid in stratification of individual patients with breast cancer before neoadjuvant chemotherapy.

The prognostic value of tumor markers in patients with glioblastoma multiforme: analysis of 32 patients and review of the literature.

Although several studies have examined brain tumor markers for prognostic value, few investigations have stratified analysis based on specific histologic grade. The objective of this study was to evaluate a single histologic grade of glioma, the grade IV glioma or glioblastoma (World Health Organization Classification), with a comprehensive panel of tumor markers in an attempt to identify those with prognostic significance. Tumor samples from a cohort of patients with glioblastoma multiforme (n=32) were examined for tumor markers, DNA analysis, and clinical variables in an attempt to determine a ‘profile’ for this tumor. We used univariate and multivariate statistical analysis to determine the prognostic value of tumor cell ploidy, percent S-phase, DNA index, p53, and Ki-67 labeling index, as well as the variables of gender, race, age, location of tumor, history of chemotherapy, and primary versus recurrent tumor. Two additional tumor markers, multidrug resistance gene 1 and glutathione-S-transferase subtype pi, were included in the sample testing, but were not analyzed statistically. Univariate analysis indicated that increasing age had a strong association with decreased survival. Female gender, increasing Ki-67, no chemotherapy before sample collection, and primary glioblastoma showed some association with decreased survival in the univariate model. The univariate results indicated that race, side of tumor, ploidy, S-phase, DNA index, and p53 had no prognostic value. Multivariate modeling demonstrated that age, gender, and Ki-67 were the strongest factors associated with survival. The relevant literature is reviewed.