M Stevens

Abstract P4-02-19: A Phase II Study of Adding the Multikinase Inhibitor Sorafenib to Existing Endocrine Therapy in Patients with Metastatic Estrogen Receptor Positive Breast Cancer

Background: Endocrine therapy for metastatic estrogen receptor (ER) positive breast cancer is effective and relatively nontoxic, but resistance eventually develops in all patients. Preclinical data suggest that growth factor signaling and angiogenesis may promote endocrine resistance and blocking such pathways may restore endocrine sensitivity and delay resistance. Methods: We conducted a phase II trial of administering sorafenib, which inhibits VEGFR and Ras/Raf/MAPK, to patients with metastatic ER-positive breast cancer after at least 3 months of antiestrogen use. Patients were required to have either stable disease or progressive non-visceral metastasis. Measurable disease was required. Sorafenib 400 mg BID was administered along with the same antiestrogen patients were already taking. A core biopsy of accessible disease was offered at entry and after 28 days of sorafenib. Serum was collected on day 1 and day 28 for VEGF, VEGFR, and VEGFR2 analysis. Primary endpoint was response rate by RECIST criteria after 3 months of sorafenib. Secondary endpoints were safety, time to progression (TTP), and biomarker assessment. Planned sample size was 43 but the study closed after 11 patients because of slow accrual. Results: Median age at entry was 45 years (Range 39-72). 7 patients were on tamoxifen, 3 on an aromatase inhibitor, and 1 on fulvestrant. Of the 11 patients enrolled, 8 had progressive disease (PD) on entry and 3 had confirmed stable disease (SD). One patient with SD at entry discontinued sorafenib after 2 weeks because of a grade 3 rash. Of the 10 patients evaluable for response, 7 had SD (70%) and 3 had PD. Two of the SD patients had minor responses, but no partial responses were seen. Median TTP after adding sorafenib was 182 days (6 months). Of the 8 patients who entered the study with progressive disease, 5 converted to stable disease (62%) with a median TTP of 136 days (4.5 months). There was a significant reduction in mean serum VEGFR2 on day 28 (P 0.0035) with borderline significant reduction of VEGFR (P 0.08). In the 7 patients with SD as best response, mean VEGFR and VEGFR2 levels were significantly reduced (P 0.016 and 0.038, respectively). There was no significant change in serum VEGF in any of the groups tested. Most common adverse events were rash in 9 patients, weight loss in 8, and hypertension in 6. Most common laboratory abnormalities were hypophosphatemia in 11 patients, hypokalemia in 9, and elevated ALT/AST in 4. The majority of toxicities were grade 1. There were 5 grade 3 toxicities; rash, anorexia, hypokalemia, and 2 hypophosphatemia. No grade 4 toxicities occurred. Overall, treatment was well tolerated and all toxicities were reversible upon sorafenib discontinuation. Tissue biomarkers including 4 paired biopsies will be examined. Conclusions: Sorafenib may prolong antiestrogen benefit in patients with metastatic ERpositive breast cancer and in particular can restore endocrine sensitivity in patients with disease progression on such therapy. Clinical trials that target endocrine resistance remain critical for understanding mechanisms of resistance and can help preserve patient quality of life by avoiding the early use of more toxic treatments. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-19.

Abstract P1-14-06: Everolimus effect on hematologic parameters in a phase II clinical trial for metastatic estrogen receptor (ER) positive breast cancer

Background: Everolimus (RAD001) is increasingly used in combination with endocrine therapy for treatment of metastatic ER-positive breast cancer. Its beneficial effect notwithstanding, familiarity with its associated toxicities is critical for the treating oncologist. Here we present hematologic changes on everolimus from a phase II trial using a combination of everolimus and fulvestrant in metastatic ER-positive breast cancer after aromatase inhibitor failure (NCT00570921). Methods: Complete Blood Counts (CBCs) were collected at baseline, 2 weeks, 4 weeks, and every 4 weeks thereafter while on treatment, as well as one month after discontinuation. Adverse events (AEs) were defined on protocol using Common Toxicity Criteria (CTC) version 3. Linear mixed modeling with random intercepts and slopes were used to study trends of studied parameters during treatment and comparisons were conducted using paired t-test. All p-values were two sided. Results: There were 31 evaluable patients on trial. Anemia was reported in 22 patients (71%), thrombocytopenia in 17 (55%), and leukopenia in 14 (45%). All toxicities were grade 1 or 2 except for one grade 3 anemia deemed unrelated to study drug. To further analyze the observed changes and trends, we next studied red blood cell indices, including mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC), as well as differential white blood cell percent distribution. Both MCV and MCH decreased significantly over time (p Conclusion: Anemia, leukopenia, and thrombocytopenia are commonly observed on everolimus, albeit predominantly mild in nature. Changes in red blood cell indices start very early after treatment and appear readily reversible upon discontinuation, suggesting that these changes may not solely be due to suppression of hematopoiesis. The etiology for these changes is currently unclear. While leukopenia is relatively common, lymphopenia in particular is consistently observed and does not appear to be readily reversible in the first month after treatment discontinuation. This may be related to the risk of infection encountered while on everolimus. Regular monitoring and familiarity with the spectrum of CBC changes observed on everolimus is prudent with its increased use. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-14-06.

Abstract P3-07-04: Impact of estrogen receptor (ER) and HER2 co-expression on breast cancer characteristics and disease presentation

Background: ER and HER2 expression can alter breast cancer biology and behavior. Rationalizing that ER-negative/HER2-negative breast cancer is the more undifferentiated form of the disease we evaluated the impact of ER expression, HER2 expression, and then their co-expression on biologic and clinical characteristics of breast cancer. Methods: We analyzed a prospectively collected data set for patients diagnosed with breast cancer at the Markey Cancer Center between January 2007 and December 2012. Out of 1257 patients with a new diagnosis of invasive breast cancer, 1187 had complete ER and HER2 biomarker data and were included in this study. Among the different phenotypic groups we compared traditional patient and disease characteristics including age, tumor size, stage, grade, nodal status, and sites of metastatic disease. Statistical significance was determined using the Chi-square test, Fishers exact test, two-sample t-test, or log-rank test as appropriate. Results: The impact of ER expression was evaluated by comparing the ER-positive/HER2-negative group (n = 762) to the ER-negative/HER2-negative breast cancer group (n = 231). ER presence was significantly associated with older age (58 vs. 53 years, p<0.0001), smaller mean tumor size (1.8 vs. 2.3 cm, p = 0.0003), lower grade (p<0.0001), earlier stage at presentation (p = 0.0002), and higher frequency of bone involvement in stage 4 disease (56.3% vs. 34.1%, p = 0.0162. There was no significant difference detected in frequency of other sites of metastatic disease. In contrast to the striking impact of ER presence, HER2 had no significant impact on any of the above parameters tested in ER-negative disease when examined by comparing the ER-negative/HER2-positive group (n = 87) to the ER-negative/HER2-negative breast cancer group. To study the impact of both ER and HER2 co-expression, we compared the ER-positive/HER2-positive breast cancer group (n = 107) to the ER-negative/HER2-negative breast cancer group. Compared to ER-negative/HER2-negative breast cancer, ER-positive/HER2-positive disease was more likely to be lower in grade (p< 0.0001), had higher risk of node positive status (51.1% vs. 36.8%, p = 0.0215) and had higher frequency of bone involvement in stage IV disease (62.5% vs. 34.1%, p = 0.0484). There were no significant differences in any of the other parameters tested. Interestingly, within the subgroup of ER-positive/HER2-positive disease, the presence of progesterone receptor (PgR) positivity (n = 73), which is considered indicative of more ER dependence, was somewhat unexpectedly associated with a younger age at time of presentation (50.85 vs.56.06 years, P = 0.0226) compared to PgR-negative disease (n = 34), with no other significant impact noted for PgR presence. Conclusion: When compared to ER-negative/HER2-negative breast cancer as the control group, ER presence is associated with more profound changes in key breast cancer characteristics than HER2 positivity. In contrast, when both ER and Her2 are co-expressed, the influence of ER is markedly attenuated by HER2, with a more dominant aggressive disease phenotype, albeit with retention of some ER features as reflected by lower grade and higher frequency of bone involvement in stage IV disease. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-04.

Abstract P2-14-05: A phase II study of combined fulvestrant and RAD001 (everolimus) in metastatic estrogen receptor (ER) positive breast cancer after aromatase inhibitor (AI) failure.

Background: Fulvestrant is used to treat women with metastatic ER-positive breast cancer after AI failure, but has a short duration of benefit. Pi3K/mTOR signaling has been implicated in preclinical models of fulvestrant resistance and recent trials suggest that everolimus, an oral inhibitor of mTOR, can overcome resistance to other forms of endocrine therapy. We hypothesized that everolimus may delay resistance to fulvestrant and prolong time to progression (TTP). Methods: We designed a phase II clinical trial of combined fulvestrant and everolimus in postmenopausal women with ER-positive breast cancer who relapsed or experienced metastatic disease progression within 6 months of AI use. Fulvestrant was given at 500 mg IM on day1, 250 mg d14, 250 mg d28, and monthly thereafter. Everolimus was given at 10 mg po daily. Patients were required to have measurable or evaluable disease with preserved performance status and adequate organ function. Primary endpoint is TTP, and secondary endpoints are safety, response rate, clinical benefit rate, and biomarker analysis. A sample size of 40 patients was calculated to meet a median TTP of 7.0 vs. 3.7 months for fulvestrant alone as reported in the EFECT trial. Patients were followed monthly for clinical and toxicity assessment and imaging was obtained every 2 months. Tumor blocks were collected when available and biopsies were offered if disease was accessible. Results: To date, 30 patients enrolled on study with a median age of 56 years (range 39–85). Most common metastatic disease sites were bone in 26 patients (87%), liver in 19 (63%), and lung in 16 (53%). Prior therapy included tamoxifen in 21 patients (70%), and chemotherapy in 20 (67%), of those 17 were in the adjuvant/neoadjuvant setting. 6 patients (20%) received more than one AI. 2 patients were ruled ineligible immediately after enrollment and starting study treatment, one because of a creatinine level outside the reference range and one because of the need for palliative radiation. Of the remaining 28 patients, 18 discontinued therapy because of disease progression, 3 because of toxicity, 2 upon patient request, and 1 because of unrelated intercurrent illness, with 4 patients currently on therapy. Most common adverse events reported were mucositis in 13 patients (43%) and rash in 11 (36%). Most common laboratory abnormalities were elevated ALT/AST in 18 patients (60%), elevated cholesterol in 13 (43%), and hypokalemia in 13 (43%). The majority of toxicities were grade I/II. Most common grade III toxicities, regardless of attribution, were infection requiring hospitalization in 3 patients (10%), hypokalemia in 3 (10%) and mucositis in 2 (7.4%). There was one grade 4 toxicity reported-hypokalemia. Overall, treatment was reasonably tolerated and toxicities manageable. Efficacy findings, including the primary endpoint of TTP, will be analyzed and presented at the meeting. Conclusions: Combined everolimus with fulvestrant is feasible and has manageable toxicities in this cohort of women with metastatic ER-positive breast cancer. Detailed efficacy analysis along with updated toxicity data will be presented at the meeting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-14-05.

P1-08-23: Characteristics of De Novo Stage IV Breast Cancer Presentation and Comparison with Stage IV Disease Relapse after Adjuvant Therapy.

Background: We hypothesized that patients diagnosed with stage IV breast cancer at presentation may have different disease characteristics than patients who develop relapsed stage IV disease after adjuvant therapy. To examine potential differences, we analyzed a prospectively collected data set for patients diagnosed at the Markey Cancer Center starting from the beginning of 2007 to date. Methods: Out of 1089 patients, we identified 76 patients (7%) who presented with de novo stage IV disease and 40 patients (4%) who experienced systemic disease relapse after initial adjuvant therapy. We compared key variables between the two groups including patient age, tumor size, grade, estrogen receptor (ER) status, progesterone receptor (PgR) status, HER2, and sites of metastatic disease involvement. Statistical significance was determined using the Chi-square test, Fisher9s exact test, two-sample t-test, or Wilcoxon9s rank sum test as appropriate. Results: Patients with de novo stage IV breast cancer were more likely to be older (median age 58.5 years, Range 28–88) than women with relapsed stage IV breast cancer (median age 53 years, Range 28–77), and this difference was statistically significant (p = 0.039). As compared to the group with relapsed disease, breast cancer presenting with de novo stage IV disease was more likely to be Grade 1/2 (43% vs. 18.4%, p=0.032), ER positive (69.7% vs. 47.5%, p= 0.019), and PgR positive (56.6% vs. 32.5%, p= 0.0136). Interestingly, de novo stage IV breast cancer was more likely to be HER2 positive than in patients with relapsed disease (27.54% vs. 10.26%, p=0.035). When available patient data prior to 2007 was included in the analysis, we observed no significant difference in the frequency of HER2 expression between the de novo and relapsed groups (27.4% vs. 19.4%, p= 0.26). In comparing sites of metastatic disease involvement, the de novo stage IV patient group was more likely to have bone metastasis than the relapsed disease patient group (68.4% vs. 35%, p = 0.0006). There were no significant differences in the frequency of other metastatic sites involved, including brain, liver, and lung. Conclusions: In this breast cancer patient cohort, there was a relatively high percentage of women presenting with stage IV disease, likely reflecting the underserved nature of this patient population. Women with de novo stage IV breast cancer were more likely to be older, have ER/PgR positive disease, and have bone metastasis as the primary site of involvement. These characteristics may reflect delay in initial presentation rather than a biologically more aggressive disease phenotype. The higher relative frequency of HER2 positive cancer in the de novo stage IV patient group is likely related to the impact of adjuvant trastuzumab use on reducing the risk of relapse in HER2 positive breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-23.

P5-13-24: A Predictive Model of Early Systemic Disease Relapse after Standard Adjuvant Therapy for Breast Cancer.

Background Early relapse after adjuvant therapy for breast cancer is very discouraging and remains a major problem. We sought to identify predictors of early relapse risk and build a predictive model for relapse using prospectively collected data for patients seen at the Markey Cancer Center starting 2007 to date. Methods: Of the 1098 new patients seen, 814 patients had stage I-III disease and were further analyzed for predictors of early relapse risk. Univariate analyses were performed for key variables including patient age, tumor size, grade, estrogen receptor (ER) status, progesterone receptor (PgR) status, and HER2 status. A multivariate Cox regression model was built to identify predictors of systemic relapse and model-building was performed using step-wise model selection to determine candidate models. A risk score was developed based on the linear combination of covariates in the final Cox model. Time-dependent predictive curves, a newly developed statistical methodology, were used to evaluate the predictive accuracy of the proposed risk score. Results: Median patient age was 57 years (Range 25–92) and 88% were white. Forty six (46) % had stage I disease, 36% stage II, and 18% stage III. Median follow up time was 2.3 years. Of this 814 patient cohort, 708 patients had complete baseline covariate data and were used to build the candidate models. The final Cox regression model included 5 covariates that were significantly associated with risk of early relapse: stage III disease (p = 0.0011), grade III (p = 0.0028), PgR-negative status (p = 0.0121), HER2−negative status (p = 0.0305), and node-positive status (p = 0.0360). These five covariates were then used to calculate an early recurrence risk score, which is the weighted average of these risk factors when present, with the weights being the coefficients from the Cox regression model. The 1-year, 2-year and 3-year predictive curves for this risk score decrease considerably, especially for the 2-year and 3-year curves, indicating good predictive accuracy of the risk score. The highest risk score group, which represents 4.8% of the population, has a 1-year, 2-year and 3-year relapse probabilities of 13.0% (95% CI: 4.1%, 27.3%), 39.4 % (95% CI: 20.1%, 58.3%), and 52.3% (95% CI: 28.5%, 71.5%), respectively. In comparison, for the overall population, the corresponding 1-year, 2-year, and 3-year relapse probabilities were only 1.1% (95% CI: 0.5%, 2.1%), 4.2% (95% CI: 2.7%, 6.1%) and 6.2% (95% CI: 4.2%, 8.6%), respectively. Conclusions: The developed risk score based on stage, tumor grade, PgR, HER2, and node status is highly predictive of early relapse in breast cancer patients after standard adjuvant therapy. Our model can be used to identify patients with high risk of early disease relapse who may otherwise benefit from enrollment on novel adjuvant therapeutic trials to improve their outcome. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-24.