Cathie T. Chung

Diagnostic and therapeutic delays among a multiethnic sample of breast and cervical cancer survivors

Several publications reporting on health disparities document that ethnic minorities disproportionately experience delays in healthcare access, delivery, and treatment. However, few studies examine factors underlying access and receipt of healthcare among cancer survivors from the patient perspective. This study explores diagnostic and therapeutic care delays among a multiethnic sample of breast and cervical cancer survivors and examines contextual factors influencing diagnostic and therapeutic care delays.

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.

Combining Emerging Agents in Advanced Breast Cancer

Newer treatments have improved survival for patients with metastatic breast cancer over the last two decades, and a battery of new cytotoxic and targeted therapies is continuing to enhance this trend. This review outlines recent data and ongoing research in this area, by highlighting new developments (regarding approved but relatively new classes of cytotoxic and targeted agents) and also new classes of targeted therapy that are undergoing clinical evaluation. Mechanisms for synergy between agents are discussed where data are available, as is information on the rationale behind the development of agents that inhibit angiogenesis, DNA repair, histone deacetylases, heat shock proteins, or various signaling pathways in tumor proliferation. The abundance of clinical research surrounding anticancer agents, together with ongoing cancer biology research, is expected to further increase the available pool of therapeutic options for metastatic breast cancer. Concomitantly, in the absence of an effective targeted monotherapy, a better understanding of the interplay between biologic and cytotoxic anticancer agents will improve our ability to rationally design combination regimens with better efficacy and tolerability.

Phase I/II Trial of Vinorelbine and Sorafenib in Metastatic Breast Cancer

PURPOSE We investigated the efficacy and toxicity of sorafenib, a multikinase inhibitor of vascular endothelial growth factor receptor tyrosine kinase, in combination with vinorelbine therapy in a phase I/II trial in patients with metastatic breast cancer. PATIENTS AND METHODS We enrolled 11 patients in the phase I portion to determine the maximum tolerated dose (MTD) of the combination, followed by 35 extra patients treated at the MTD in phase II. The median age of patients was 54 years old (range, 31-72 years old). Tumors were estrogen receptor and progesterone receptor (ER/PR) positive in 54% (22/54) of patients, and triple negative (ER(-), PR(-), HER2(-)) in 41% (17/54) of patients. Of all patients, 22% received sorafenib and vinorelbine as first-line therapy, 37% as second-line therapy, and 41% as third-line therapy. RESULTS In total, 41 patients were treated at the MTD (6 during phase I; 35 in phase II). The observed 44% 4-month progression-free survival rate was similar to the estimated historical rate of 43% with vinorelbine treatment. The combination was tolerated with expected toxicities. Patients treated at the MTD who had received prior bevacizumab treatment received a median of 1.5 cycles (range, 1-10 cycles) compared with a median of 5 cycles (range, 2-12 cycles) for patients without prior bevacizumab treatment. CONCLUSION Further evaluation of vinorelbine and sorafenib in bevacizumab-naive patients may be of interest if specific biomarkers guiding patient selection can be identified.

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.

Abstract P6-12-07: Phase II Trial of Vinorelbine and Sorafenib in Metastatic Breast Cancer (MBC)

BACKGROUND Vinorelbine, a semisynthetic vinca alkaloid, at 20-25mg/m2 has a response rate of 15-30% for second line therapy of MBC. Sorafenib is an oral multi-kinase inhibitor against the tyrosine kinases for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), Flt-3 and c-Kit receptors. In preclinical studies, sorafenib demonstrated anti-tumor activity by inducing complete tumor stasis in a variety of tumor types through the Raf/MEK/ERK pathway. In the NCI H460 cell line for NSCLC tumor xenograft, synergy between vinorelbine and sorafenib were observed. We established the phase II recommended dose in MBC for the combination of vinorelbine (d1,18,15 on a 28 day cycle) with daily sorafenib at vinorelbine 20mg/m2 and sorafenib 200mg oral twice daily (reported at ASCO 2010). Phase II trial will complete in 6/2010. METHODS Eligibility include: MBC with adequate end-organ function and performance status 0-2 who have up to two lines of prior chemotherapy regimens. Patients were treated at the recommended phase II dose as above. Tumor response was evaluated every two cycles by RECIST criteria. N=39 (target accrual 41 by 6/10) patients enrolled at the above recommended dose from 6/09 to 6/10. Treatment was continued until disease progression or unacceptable toxicity. RESULTS Sites of metastatic disease included liver, lung, bone, bone marrow and skin. A total of 22/39 patients were enrolled prior to 2/17/2010 and are therefore evaluable for 4-month progression free survival (PFS) evaluation at this time. Median age of these patients was 56 yrs (range 39-72). ECOG performance status is 0 in 8 and 1 in 14 participating patients. Prior number of chemo regimens for MBC was 0 (n=4), 1 (n=10), and 2 (n=8). There was 1 partial response (PR) with 2 prior, and 8 stable disease (SD) with PFS for more than 4 months with 6 with 1 prior and 2 with 2 prior regimens for MBC. A total clinical benefit rate (PR+ SD) of 9/22 (41 %). SD patients included 1 who progressed at 11 months (1 prior), and 3 still on therapy. The patient with SD for 11 months previously progressed in 2 months on abraxane. Toxicities resulted in treatment discontinuation in only 2 patients. Toxicities include: Grade 3 hand-foot reaction (n=3), Gr 4 ANC (n=3), Gr 3 fatigue (n==3), Gr 3 Diarrhea (n=2), Gr 3 hypertension (n=2), Gr 3 infection (n=3), 2 skin), Gr 3 elevated lipase (n= 1), Gr 3 hypophosphatemia (n=2), Gr 3 hyponatremia (n=2), Gr 3 Somnolence (n=1), Gr 4 PLT (n=1), Gr 3 back pain (n=1), and Gr 3 cough (n=1). CONCLUSIONS The addition of sorafenib to vinorelbine to date showed a promising 41% clinical benefit rate in this heavily pretreated MBC population with a tolerable toxicity profile. Follow-up is continuing, we will report on the entire cohort of 41 patients at SABCS. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-07.

Abstract P2-14-08: The Pilot Trial of Intermittent Exemestane Therapy for Metastatic Breast Cancer

Background: While aromatase inhibitors are effective for ER/PR positive breast cancer, resistance frequently develops. EXE is a steroidal AI and has a weak hormone-like activity. Long-term EXE treatment up-regulated amphiregulin-mediated EGFR activation and EXE resistance could result from ER-EGFR cross-talk. In cell culture and animal studies, acquired resistance to EXE was significantly delayed with intermittent use, associated with decreased production of amphiregulin. For first line therapy in MBC, EXE had a median progression free survival (PFS) of 10 mos. As second and third line therapies, PFS decreased to 4.7 mos and 2 mos, respectively. After ≥ 2 of prior endocrine therapy, PFS to EXE ranged between 3.4 mos to 3.7 mos. The rationale for this study was that after long-term estrogen deprivation clinically equivalent to long-term exposure to AI, estrogen may induce apoptosis. With intermittent EXE use, we hope to delay the acquired AI resistance. Methods: Aims were to: 1) assess the PFS and 2) compete response (CR), partial response (PR) and clinical benefit rate [CBR=CR +PR + Stable disease (SD)≥ 6 mos], assessment of toxicity, compliance with medication adherence, and quality of life with assessment of bone health. The study included: 1) ER/PR positive MBC in first, second line/third line hormonal therapy, and one prior chemotherapy for MBC with no prior EXE allowed. EXE was given 25 mg daily × 14 days then 7 days off treatment, each 21-day cycle, imaging was done after every three cycles. Correlatives with estradiol level were drawn at day 1 and day 15 in each cycle. Results: From June 2008 to 2012 we enrolled 33 MBC patients ER/PR positive MBC with a median age of 60 yrs (42–79). At this cut off data date, 2 were inevaluable due to incidental colon cancer and change in treatment choice. 17 patients received treatment as first line (52%), 10 as second or third line hormonal therapy (30%), and 6 who received chemotherapy for MBC (18%). Median PFS and (95% CI) was 6.2 mos (1.9–12.2), 4.2 mos (2.1–10.1), and 3.2 mos (2.1-NR), respectively. For first line patients, there were 3 PRs and 4 with SD>6 mos for a CBR of 7/14 (50%). For second/third line, there were 3 with SD>6 mos for a CBR of 3/9(33%), no response seen in the prior chemotherapy group. The major metastatic sites included bone, liver, lung. 4 patients were Her2+ (13%). Adverse effects including hot flashes (62%), insomnia (31%), nausea (24%), bone pain (17%), fatigue (41%), joint pain (31%) were observed. Median number of cycles delivered is 6 (2–24) for first line, 5.5 (1–15) for second/third line, and 5 (2–9) for prior chemotherapy. Correlatives and QOL assessments are ongoing. Conclusions: Compared to the standard continuous EXE, PFS and CBR is inferior in the intermittent EXE as first line therapy, as second and third line therapy, the median PFS was 4.2 comparable to reported 3.7 mos with the CBR was 33% to 31.5% observed in the EFFECT trial. Interestingly, hot-flash rate was much higher at 62% compared to 11.2% in the EFFECT trial. Arthralgia is comparable at 31%. Patients who already received chemotherapy do not appear to respond favorably to intermittent hormonal therapy. Full response data with correlatives regarding the estradiol levels will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-14-08.

P5-19-05: Age-Related Changes in the Pharmacokinetics (pK), Response, and Toxicity of Weekly nab-Paclitaxel in Patients with Metastatic Breast Cancer (MBC).

Background: Although cancer is a disease of aging, few studies have evaluated the association between patient age and the pK or pharmacodynamics (pD) of cancer therapeutics. The goals of this study were 1) to evaluate the age-related changes in the pK and pD of weekly nab -paclitaxel in patients with MBC; 2) to determine response rate; and 3) to explore the relationship of age with pK and pD parameters (i.e., dose reductions, dose delays and grade ≥ 3 toxicities). Patients and Methods: Forty patients with MBC, receiving 1 st or 2 nd line chemotherapy, entered an IRB approved protocol to evaluate the age-related changes in the pK of weekly nab -paclitaxel administered at 100 mg/m 2 IV for 3 weeks followed by a 1-week break. Patients were accrued from 4 age strata 70 years of age. Blood samples were collected for pK analysis with the first dose of nab -paclitaxel. Response was assessed every 2 cycles. Toxicity was graded using the NCI Common Toxicity Criteria for Adverse Events (v 3.0) and was adjudicated as attributable to nab -paclitaxel if it was possibly, probably, or definitely related. Linear regression analysis was used to examine the strength of the relationship between patient age and natural logarithm of 24 hour area under the curve (AUC). Two-sided two-sample t-tests were used to assess if there was a difference in mean age based on the presence of pD variables (i.e., dose reductions, dose delays and grade ≥ 3 toxicities). The significance level was set to 0.05. Results: Of the 40 patients who entered the study, 39 (98%) were evaluable with a mean age of 60 (SD=13.4; min=30; max=81). Patients were accrued in the following age cohorts: 70 (n= 9; 23%) years of age. The median number of courses completed was 4 (min=1, max=21). The response rate was: 0% (n=0) CR, 31% (n=12) PR, 38% (n=15) SD. Grade 3 toxicity was experienced by 26% (n=10). We observed 8% (n=3) grade 3 hematological toxicities [neutrophils (n=1; 3%), leukocytes (n=2; 5%)] and 18% (n=7) grade 3 non-hematological toxicities [nausea and hypophosphatemia (n=1; 3%), diarrhea and infection without neutropenia (n=1; 3%), fatigue (n=2; 5%), hyponatremia (n=1; 3%), and infections without neutropenia (n=2; 5%)]. There were no cases of grade 4 or 5 toxicity. Grade 2 sensory neuropathy was experienced by 8% (n=3; no cases in the 70+ age cohort). Dose reductions or course delays were experienced by 62% (n=24) and 21% (n=8), respectively. There was a borderline significant positive association between age and natural logarithm of total nab -paclitaxel 24 hour AUC (coef=.01; se=.006; p=0.055; n=36). There were no differences in the mean ages based on the presence of grade 3 or higher toxicity (p =0.75), need for dose reductions (p=0.48), or need for dose delays (p=0.61). Discussion: There is a borderline statistically significant relationship between age and 24 hour AUC but no differences in mean age based on pD variables (i.e., dose reductions, dose delays and grade ≥ 3 toxicities) were identified. The treatment is well-tolerated across all age groups. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-05.

Follow-Up Strategies After Breast Cancer Treatment

For many patients with early-stage breast cancer who have been accustomed to the security from frequent physician visits, as required during the delivery of primary breast cancer therapy including surgery, radiation and systemic adjuvant therapy, the transition to routine follow-up care can be especially anxiety-provoking. In the United States, there are over two million breast cancer survivors, and between 1975 and 2003, there continued an upward trend in 5-year relative survival rates for female breast cancer, reaching 89%. This underscores the need to deliver cost-effective follow-up care to breast cancer patients, as guided by evidence-based medicine. Such care should incorporate interventions based on their potential beneficial effects on relieving patient symptoms and improving survival, while balancing potential detrimental effects on patient quality of life/anxiety when, for example, select interventions have shown no health benefits. This chapter outlines follow-up strategies after acute treatment for breast cancer has ended.

Barriers to treatment in patients with locally advanced breast cancer.

6040 Background: Despite a decrease in breast cancer (BC) mortality, partly due to increased awareness and more effective screening, many patients (pts) still present for treatment after extended delays. We set out to identify reasons why pts encounter delays in initiating oncologic treatment, once symptoms appear. Methods: A 39-item Likert-scale questionnaire was administered to pts with stage III BC who had experienced a 3-month or greater delay in diagnosis or initiation of oncologic treatment from time of onset of symptoms. Results: Forty pts (median age 52; range: 30-78) completed the questionnaire. Of these, there were 32.5% Caucasian, 47.5% Hispanic, 12.5% Black and 7.5% Asians. Pts experienced 13 to 74 week-delay (mean = 25.78) to oncologic treatment. Barriers to treatment were divided into the following categories: patient barriers: The most commonly reported barrier among participants was “waiting for the scheduled visit to get results” (47.5%). Additional barriers included the fear of losing th...