Age-related changes in nanoparticle albumin-bound paclitaxel pharmacokinetics and pharmacodynamics: influence of chronological versus functional age.

PURPOSE: This study evaluated age-related changes in pharmacokinetic and pharmacodynamic parameters of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in patients with metastatic breast cancer. METHODS: Forty patients received nab-paclitaxel (100 mg/m(2) weekly for 3 weeks followed by a 1-week break) as first- or second-line chemotherapy. Blood samples were collected for analysis, and response was assessed every two cycles. Planned statistical analyses included linear regression to examine the relationship between age and pharmacokinetic variables (ln clearance [CL] and ln area under the curve [AUC]) and two-sided two-sample t tests to evaluate age differences in pharmacodynamic variables. The association between chemotherapy toxicity risk scores and pharmacokinetic and pharmacodynamic variables including grade ≥ 3 toxicity were examined post hoc. RESULTS: Of 40 patients enrolled, 39 (98%) were evaluable (mean age: 60 years; range: 30-81 years). A partial response was achieved in 31%, and 38% had stable disease. There was a borderline positive association between age and 24-hour ln AUC (slope = 0.011; SE = 0.006; p = .055). Grade 3 toxicity was experienced by 26% (8% hematologic, 18% nonhematologic). There were no differences in age based on the presence of grade 3 toxicity (p = .75), dose reductions (p = .38), or dose omissions (p = .15). A significant association was noted between chemotherapy toxicity risk score category and presence of grade 3 toxicity (toxicity rate by risk score category: low, 5 of 30 patients; medium, 3 of 6 patients; high, 2 of 3 patients; p = .041). CONCLUSION: A borderline significant relationship exists between age and 24-hour AUC, but no differences were noted for pharmacodynamic variables (grade 3 toxicity, dose reductions, or dose omissions) based on age. There is an association between toxicity risk score and grade ≥ 3 chemotherapy toxicity and pharmacokinetic variables. The treatment is well tolerated across all age groups.

Impact of multifocality and lymph node metastasis on the prognosis and management of microinvasive breast cancer.

BACKGROUND: There are few data on the long-term outcome of patients with microinvasive (T1mi) breast cancer. Moreover, predictors of lymph node involvement and the impact of multifocal microinvasion are not well understood. METHODS: Patients with T1mi cancer, defined as tumors ≤1 mm, surgically managed at our institute and who underwent axillary lymph node evaluation were identified. Specimen slides were independently reviewed. Multivariate analysis was used to identify factors predictive of lymph node involvement. RESULTS: Forty-five patients with T1mi cancer were identified. Median patient age was 52 years, and median size of in situ disease was 4 cm. Nine tumors (20.0 %) had more than one focus of microinvasion. Lymph nodes metastasis were identified in 9 patients: 1 macrometastasis (2.2 %), 4 micrometastases (8.9 %), and 4 isolated tumor cells (8.9 %). Seven of 9 patients with lymph node involvement underwent adjuvant chemotherapy. Estrogen receptor-negative invasive disease was a significant predictor of lymph node metastasis by multivariable analysis (p < 0.02). There was also a trend toward lymph node involvement in patients with multifocal microinvasion compared to unifocal disease (33.3 vs. 16.7 %, respectively). At a median follow-up of 83 months, 3 patients (6.3 %) had disease recurrence (1 local, 1 distant, 1 local and distant). All patients with recurrence initially had tumor-free lymph nodes and only one focus of microinvasion. CONCLUSIONS: Microinvasive breast cancer clearly has the ability to metastasize and recur, but in this series, only 2 % of patients with nodal macrometastasis. Only two patients experienced local recurrence, neither of whom had lymph node metastasis. The importance of identifying nodal micrometastasis in T1mi disease needs to be further explored.

Barriers to treatment in patients with locally advanced breast cancer.

Delays between presentation and treatment could have a significant effect on breast cancer mortality. The authors hypothesized that patient, physician, and system barriers are all responsible for treatment delays. Therefore, a study was conducted to define prevalent barriers to treatment from the patient's perspective. A modified 43-item Likert-scale questionnaire was administered to patients with clinical stage III locally advanced breast cancer (LABC) who had experienced a delay in treatment of 3 months or more. Between October 2008 and January 2010, 153 patients presented with LABC; 43 patients (28.1%) met eligibility, and 40 completed the questionnaire. Among the patient barriers reported, 38% of patients delayed care for fear of losing their breast and 47% awaited previously scheduled routine appointments instead of seeking care. Among the physician barriers reported, 20% of physicians of initial contact did not believe the breast lump/symptom was related to cancer and 15% did not believe it needed a biopsy. Among the system barriers reported, the most prevalent were delays in performing diagnostic tests and obtaining insurance authorization for tests, treatment, or physician visits. Substantial delays were seen in 28.1% of patients from presentation to when they sought therapy at City of Hope Comprehensive Cancer Center. The high prevalence of patient barriers versus physician/system barriers suggests that increased educational efforts for patients and health care professionals are needed.

Perspectives and attitudes on the use of adjuvant chemotherapy and trastuzumab in older adults with HER-2+ breast cancer: a survey of oncologists.

BACKGROUND: Substantial evidence supports the use of adjuvant trastuzumab with chemotherapy for patients with human epidermal growth factor receptor (HER)-2(+) breast cancer; however, a lesser amount of data is available to guide use of this therapy in older patients and in those with significant medical comorbidities. The goal of the current study was to understand how patient age and health status impact oncologists' decisions to recommend adjuvant therapy in older women with HER-2(+) breast cancer. METHODS: Medical oncologists (n = 151) participated in an online survey regarding treatment recommendations for a hypothetical patient of varying age and health status with tumor stage 2, nodal stage 2, estrogen receptor-negative, HER-2(+) breast cancer. Survey respondents recommended either chemotherapy plus trastuzumab, chemotherapy alone, trastuzumab alone, or no therapy. The effect of age and health status on therapeutic recommendations was assessed. FINDINGS: As the hypothetical patient's age increased or health status deteriorated, oncologists were less likely to recommend a combination of chemotherapy plus trastuzumab. In contrast, oncologists were more likely to recommend either trastuzumab alone or no therapy for patients with advanced age and deteriorating health status. Chemotherapy alone was recommended by only 7.5% of respondents, on average. INTERPRETATION: With limited evidence-based data for the treatment of older women with early-stage HER-2(+) breast cancer, medical oncologists recommend a diverse array of therapeutic approaches. With increasing age and declining health status they were less likely to recommend chemotherapy plus trastuzumab and more likely to recommend single-agent trastuzumab or no therapy.

Breast cancer-specific mortality after invasive local recurrence in patients with ductal carcinoma-in-situ of the breast.

BACKGROUND: Previous studies on the efficacy of primary treatments for ductal carcinoma-in-situ (DCIS) have focused on local recurrence rates. Our objective was to detail the outcomes of local invasive recurrence, distant recurrence, and breast cancer mortality in patients previously treated for DCIS. METHODS: Clinical, pathologic, and outcome data were collected prospectively for 1236 patients with pure DCIS accrued from 1972 through 2005. RESULTS: There were 150 recurrences (87 DCIS and 63 invasive). Invasive local recurrence after mastectomy was rare (0.5% of patients) and after breast preservation was more frequent (12.0% of patients). The 12-year probabilities of breast cancer-specific mortality after mastectomy and after breast preservation were 0.8% and 1.0%, respectively. The 12-year breast cancer-specific mortality and distant disease probability for the 63 patients with invasive recurrences were 12% and 15%, respectively. CONCLUSIONS: Regardless of initial treatment, most patients with invasive local recurrence after treatment for DCIS can be treated and cured.

Adjuvant aromatase inhibitors following tamoxifen for early-stage breast cancer in postmenopausal women: what do we really know?

Adjuvant hormonal therapy in the treatment of women with early-stage, hormone receptor (HR)-positive breast cancer is now considered the standard of care. Adjuvant tamoxifen decreases the risk of breast cancer recurrence and death in women with early-stage breast cancer when taken for 5 years. The benefits of tamoxifen are counterbalanced by toxicities including an increased risk of endometrial cancer and thromboembolic events. The selective aromatase inhibitors (AIs)--including anastrozole, letrozole, and exemestane--are challenging the role of tamoxifen as the adjuvant hormonal therapy of choice in postmenopausal women. Results of the Arimidex and Tamoxifen Alone or in Combination trial favor the use of anastrozole over tamoxifen as initial adjuvant hormonal therapy, with improvement in disease-free survival (DFS) and a favorable toxicity profile. The results of 2 large adjuvant trials using AIs sequentially with tamoxifen in postmenopausal women with early-stage, HR-positive breast cancer have been reported. The MA-17 study randomized women to placebo or letrozole for 5 years after completion of 4.5-6 years of initial tamoxifen. The Intergroup Exemestane Study (IES) randomized women following 2-3 years of adjuvant tamoxifen to continue to receive tamoxifen or switch to exemestane for a total of 5 years of adjuvant hormonal therapy. The MA-17 and IES trials demonstrated superior DFS with the AI and corroborated the smaller GROCTA-4B and Italian Tamoxifen Arimidex trials, which studied sequential therapy with aminoglutethamide or anastrozole. There is now substantial medical evidence supporting the use of AIs in postmenopausal women with early-stage, HR-positive breast cancer.

Phase II trial of anastrozole plus goserelin in the treatment of hormone receptor-positive, metastatic carcinoma of the breast in premenopausal women.

PURPOSE: To explore the antitumor activity of the aromatase inhibitor, anastrozole, in the treatment of premenopausal women with hormone receptor-positive, metastatic breast cancer who have been rendered functionally postmenopausal with the use of the luteinizing hormone-releasing hormone agonist, goserelin. PATIENTS AND METHODS: Premenopausal women with estrogen and/or progesterone receptor-positive, metastatic or recurrent breast cancer were enrolled in this prospective, single-arm, multicenter phase II trial. Patients were treated with goserelin 3.6 mg subcutaneous monthly and began anastrozole 1-mg daily 21 days after the first injection of goserelin. Patients continued on treatment until disease progression or unacceptable toxicity. RESULTS: Thirty-five patients were enrolled of which 32 were evaluable for response and toxicity. Estradiol suppression was assessed, with mean estradiol levels of 18.7 pg/mL at 3 months and 14.8 pg/mL at 6 months. One participant (3.1%) experienced a complete response, 11 (34.4%) experienced partial response, and 11 (34.4%) experienced stable disease for 6 months or longer for a clinical benefit rate of 71.9%. Median time to progression was 8.3 months (range, 2.1 to 63+) and median survival was not been reached (range, 11.1 to 63+). The most common adverse events were fatigue (50%), arthralgias (53%), and hot flashes (59%). There were no grade 4 to 5 toxicities. CONCLUSION: The combination of goserelin plus anastrozole has substantial antitumor activity in the treatment of premenopausal women with hormone receptor-positive metastatic breast cancer.

Role of age and health in treatment recommendations for older adults with breast cancer: the perspective of oncologists and primary care providers.

PURPOSE: To determine the impact of age and health status on adjuvant treatment recommendations for older patients with breast cancer from the perspective of medical oncologists and primary care physicians with geriatric expertise. PATIENTS AND METHODS: One hundred fifty-one oncologists and 158 primary care physicians with geriatric expertise participated in an online survey. The survey described hypothetical patients of varying ages (70, 75, 80, and 85 years) and health status (good, average, and poor) who had node-positive, hormone receptor-positive, human epidermal growth factor receptor 2 (HER-2)/neu-negative; and hormone receptor-negative, HER-2/neu-positive breast cancers. The effects of patient age and health status on the survey participants' adjuvant treatment recommendations were examined using generalized estimation equation methods. RESULTS: The majority of both oncologists and primary care physicians recommended some form of adjuvant therapy for patients of all ages (70, 75, 80, and 85 years) and health status. Both oncologists and primary care providers were less likely to recommend adjuvant treatment as a patient's age increased or health status declined (P < .0001). There were no significant differences in treatment recommendations among primary care physicians and oncologists for patients with hormone receptor-negative, HER-2/neu-positive tumors (P = .54). However, primary care providers were more likely than oncologists to recommend no adjuvant treatment for patients age 75 years or older with hormone receptor-positive, HER-2/neu-negative tumors (P < .01). CONCLUSION: Age and health status influence oncologists' and primary care providers' adjuvant treatment recommendations. Evidence-based guidelines for breast cancer treatment in older adults taking into account age and health status are needed.

Goals and objectives in the management of metastatic breast cancer.

Patients with metastatic breast cancer consist of a heterogeneous group of patients whose prognoses and clinical courses can vary depending on host factors, such as comorbidity and age, and on tumor factors, such as hormone-receptor status, grade, and anatomical site of disease. Although the median survival time for patients with metastatic breast cancer is 2-4 years, subsets of patients with either indolent or limited metastatic disease may have prolonged survival times. Further, expectations of treatment, both in terms of efficacy and of toxicity, vary greatly based upon the specific treatment, patient characteristics, and tumor characteristics. Thus, the goals of treatment for patients with metastatic breast cancer are influenced by estimates of prognoses as well as a balance between physician and patient preferences regarding efficacy and toxicity considerations. Traditionally, objective measures of response and survival have been the targeted end points in clinical trial design and in physician selection of therapy for metastatic breast cancer. More recently, issues of quality of life have surfaced as important end points, especially from the perspective of the patient. The decision-making process in selecting the optimal treatment for patients with metastatic breast cancer is, therefore, a multidimensional process involving subjective as well as objective goals of treatment. Ultimately, the benefits of treatment must justify the risks and toxicities of the treatment, and the impact of treatment should be measured in relation to specified goals. Both physician and patient perspectives are important in establishing the objectives of treatment, and this process is optimally an interactive and ongoing process throughout the course of disease.

The role of aromatase inhibitors in early breast cancer.

The role of hormonal therapy for the treatment of patients with early stage breast cancer has been evaluated in many studies. The results of these studies establish tamoxifen as the gold standard of hormonal therapy for the adjuvant treatment of hormone receptor-positive invasive breast cancer in pre- and postmenopausal women. Studies show tamoxifen reduces the risk of invasive breast cancer in women at increased risk for the disease, including women with ductal carcinoma in situ. Tamoxifen has adverse effects such as hot flashes, increased risk of uterine cancer in postmenopausal women, and rare occurrence of thromboembolic disease. Despite the multiple therapeutic roles of tamoxifen, alternatives are needed. Aromatase inhibitors (AI) are drugs with antiestrogenic activity. AIs function by inhibiting the peripheral conversion of adrenally synthesized androstenedione to estradiol through inhibition of the aromatase enzyme. AIs do not suppress estradiol synthesis by the ovary adequately. Therefore, AIs are effective in reducing circulating estradiol levels in postmenopausal women, but not premenopausal women. Selective nonsteroidal AIs, including anastrozole (Arimidex; AstraZeneca, Wilmington, DE) and letrozole (Femara; Novartis, East Hanover, NJ), and the steroidal AI exemestane (Aromasin; Pharmacia, Peapack, NJ) have been associated with increased specificity and improved therapeutic index compared to nonselective AIs such as aminoglutethamide. Nonsteroidal and steroidal AIs have demonstrated to be superior to megestrol acetate in second-line therapy of postmenopausal women with metastatic breast cancer, and selective nonsteroidal AIs have shown to be superior to tamoxifen in first-line therapy of postmenopausal women with metastatic breast cancer. The ATAC (Arimidex, tamoxifen, alone, or in combination) trial is the only published randomized trial comparing the efficacy of an AI to tamoxifen for the adjuvant treatment of women with early breast cancer. This large study showed that at a median follow-up time of 33 months, anastrozole alone results in significant improvement in disease-free survival rates, reduction in contralateral breast cancers, and increased tolerability, compared to tamoxifen in postmenopausal women. Although the long-term effects of AIs are not known, the early positive results of the ATAC trial led to the approval of anastrozole by the US Food and Drug Administration for use as adjuvant hormonal therapy for postmenopausal women with hormone receptor-positive invasive breast cancer. Thus, there is an alternative to tamoxifen for postmenopausal women with relative/absolute contraindications to tamoxifen use or patients who choose not to take tamoxifen because of its side-effect profile. New AIs may challenge the position of tamoxifen as the gold standard for the treatment of early stage breast cancer in postmenopausal women.