Moreno‐Aspitia, Alvaro

Abstract Background Tumors that are negative for estrogen and progesterone receptors and do not over express HER2 are referred as “triple negative” breast cancer (TNBC). These tumors are characterized by unique molecular profiles on gene expression arrays, aggressive behavior with a high recurrence rate, an increased risk of visceral metastases, poor prognosis and lack of targeted therapies. Brostallicin is a novel synthetic compound from the class of DNA minor groove binding (MGB) anti-cancer agents. It retains activity in cancer cells resistant to alkylating agents, topoisomerase I inhibitors and is fully active against DNA-mismatch repair deficient tumor cells. Cells expressing relatively high glutathione/glutathione S-transferase (GSH/GST) levels are more susceptible to brostallicin antitumor efficacy. Cisplatin administration increases expression of GST in tumor cells leading to an increased anti-tumor efficacy of brostallicin. Trial design: Single-stage phase II study — based on the effects of cisplatin on GSH/GST levels in preclinical models, the most reasonable sequence to explore was cisplatin on Day 1 followed by brostallicin on Day 2 repeated every 21 days. Eligibility criteria: Women or men ≥18 years of age with confirmed adenocarcinoma of the breast with clinical evidence of measurable metastatic disease and triple negative subtype according to current ASCO CAP guidelines [ER/PR ≤1%; HER2 negative), who received 0–4 prior chemotherapy regimens in the metastatic setting; with adequate hematologic, renal and hepatic functions; and no active CNS metastases. Aims: To study the efficacy of the novel drug, brostallicin, as well as to serve as proof of concept of its mechanism of action in TNBC. The primary endpoint is to evaluate clinical efficacy of the combination of brostallicin and cisplatin in the treatment of patients with metastatic TNBC, as measured by progression-free survival (PFS) at 3 months with 89% power (0.10 significance level) to detect an absolute difference of 20%. Secondary endpoints include ORR by RECIST, duration of response, 6-month PFS, overall survival (OS) and adverse event profile. Tertiary endpoints include assessment of 1) GSH levels prior to the administration of cisplatin and of brostallicin; and 2) the prevalence of BCRA-1 mutation by IHC in the primary or metastatic tumor. Statistical methods: The largest 3-month PFS proportion where the proposed treatment regimen would be considered ineffective in this population was estimated at 35% based on the median PFS of 60 days in patients with metastatic TNBC enrolled in the N0234 trial (erlotinib and gemcitabine as 1st/2nd line), and the smallest 3-month PFS success proportion that may warrant subsequent studies with the proposed regimen in this patient population was estimated at 55%. The interim analysis will be reported when the 20th eligible patient has been followed for 3 months. Present accrual and target accrual: 21 patients have been accrued at the time of abstract submission (June 2011). Target accrual is 42 evaluable patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-14.

There is an ongoing need for development of new chemotherapeutic regimens for metastatic breast cancer [mBC], especially when tumors lack therapeutic targets such as the estrogen or progesterone receptor [ER/PR], or the human epidermal growth factor receptor-2 [HER2]. Capecitabine is an orally bioavailable fluoropyrimidine approved for monotherapy in mBC, and bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor which has shown to be active in mBC and tolerable in combination with other chemotherapeutics. The combination of these two agents has been explored in multiple phase II and III clinical studies, with improvements in progression-free survival and overall response rates noted as compared to capecitabine monotherapy. However, the use of bevacizumab in combination with capecitabine and other chemotherapy agents for mBC remains beset with controversy due to safety concerns, cost issues, and pending regulatory decisions.

Purpose NCCTG (North Central Cancer Treatment Group) N9831 is the only randomized phase III trial evaluating trastuzumab added sequentially or used concurrently with chemotherapy in resected stages I to III invasive human epidermal growth factor receptor 2–positive breast cancer. Patients and Methods Patients received doxorubicin and cyclophosphamide every 3 weeks for four cycles, followed by paclitaxel weekly for 12 weeks (arm A), paclitaxel plus sequential trastuzumab weekly for 52 weeks (arm B), or paclitaxel plus concurrent trastuzumab for 12 weeks followed by trastuzumab for 40 weeks (arm C). The primary end point was disease-free survival (DFS). Results Comparison of arm A (n = 1,087) and arm B (n = 1,097), with 6-year median follow-up and 390 events, revealed 5-year DFS rates of 71.8% and 80.1%, respectively. DFS was significantly increased with trastuzumab added sequentially to paclitaxel (log-rank P < .001; arm B/arm A hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.85). Comparison of arm B (n = 954) and arm C (n = 949), with 6-year median follow-up and 313 events, revealed 5-year DFS rates of 80.1% and 84.4%, respectively. There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration (arm C/arm B HR, 0.77; 99.9% CI, 0.53 to 1.11), but the P value (.02) did not cross the prespecified O'Brien-Fleming boundary (.00116) for the interim analysis. Conclusion DFS was significantly improved with 52 weeks of trastuzumab added to adjuvant chemotherapy. On the basis of a positive risk-benefit ratio, we recommend that trastuzumab be incorporated into a concurrent regimen with taxane chemotherapy as an important standard-of-care treatment alternative to a sequential regimen.

Abstract Purpose: To investigate the associations between baseline and posttreatment circulating tumor cell (CTC) gene expression and outcome of patients enrolled in four North Central Cancer Treatment Group metastatic breast cancer (MBC) trials in which specimens were shipped (at 4°C) from community-based sites to a reference laboratory (Mayo Clinic, Rochester, MN). Experimental Design: Blood was collected at treating sites from MBC patients before (baseline), during, and at the end of treatment with erlotinib + gemcitabine (N0234), sorafenib (N0336), irinotecan + cetuximab (N0436), or paclitaxel-poliglumex + capecitabine (N0437). CTCs from 10 mL of EDTA blood were enriched with CD45 depletion, 24 to 30 hours postblood collection. Reverse transcription/quantitative PCR was used to determine cytokeratin-19 (CK19) and mammaglobin (MGB1) mRNA levels in CTCs from up to 13 (N0234), 16 (N0336), 18 (N0436), and 39 (N0437) patients. The gene expressions were normalized to β2-microglobulin and calibrated to healthy blood using the 2–ΔΔCq algorithm; positivity was defined as 2 or more. Results: CK19+mRNA cells were detected in 56% to 75% and MGB1+mRNA cells in 23% to 38% of 86 patients at baseline. CK19+mRNA cells were detected in 30% to 67% and MGB1+mRNA cells in 14% to 64% of 110 postbaseline serial samples. The presence of baseline CK19+mRNA cells (P = 0.01) but not MGB1+mRNA cells (P = 0.14) was significantly associated with shorter overall survival. A decrease in MGB1+mRNA levels (baseline-week 8) seemed to be associated with clinical response (P = 0.05). Conclusions: CTC gene expression analysis conducted by a reference laboratory is feasible when blood is collected from treating sites and processed 24 to 30 hours postcollection. The presence of baseline CK19+mRNA CTCs was associated with poor prognosis; a decrease in MGB1+mRNA CTCs may help predict response to therapy of MBC patients. Clin Cancer Res; 17(22); 7183–93. ©2011 AACR.

Abstract Background: Microtubules are crucial for spindle formation during mitosis and for cellular proliferation. The antineoplastic effect of paclitaxel is mainly related to its ability to bind the beta subunit of tubulin, thus preventing tubulin chain depolarization and inducing apoptosis. Tubulins are expressed in human peripheral nerves and the binding of paclitaxel to tubulin may lead to neuropathy. Peripheral neuropathy is a common dose limiting toxicity of paclitaxel. We hypothesized that the occurrence of peripheral neuropathy may correlate with outcome (disease-free survival; DFS).Methods: This analysis sought to describe incidence of peripheral neuropathy following paclitaxel and its association to outcome (DFS) in patients who received paclitaxel (weekly x 12) in the adjuvant HER2+ intergroup trial N9831. Only eligible pts who initiated paclitaxel and did not have peripheral neuropathy at initiation of paclitaxel that were randomized to arms A (955 pts; chemotherapy alone) and C (889 pts; chemotherapy plus concurrent trastuzumab) of N9831 were included. Cox regression analysis stratified by ER/PR status and nodal status was used to compare DFS within arm between patients with and without peripheral neuropathy.Results: Out of 1844 eligible pts, 379 developed neuropathy (20.5%). For pts in arm A, those who developed neuropathy had better DFS than pts who did not (3 yr DFS: 86.2% vs 81.8%; HR 0.65; p=0.01), despite lower doses of paclitaxel in the pts with neuropathy. Grade of neuropathy did not appear to impact DFS. No statistical difference was noted for pts treated in the trastuzumab-containing arm (3 yr DFS: 92.8% vs 91.1% for pts with neuropathy vs not; HR 0.79; p=0.34). There were no differences in paclitaxel dose intensity between arms A and C.Conclusion: Patients with early stage HER2+ breast cancer who received adjuvant paclitaxel-containing chemotherapy in arm A and developed peripheral neuropathy had a better DFS than pts who did not develop neuropathy. This effect was possibly abrogated by the use of trastuzumab in Arm C. This side effect may represent effective bindings of paclitaxel to the target tubulin, lack of point mutations in tubulin at the paclitaxel binding site and/or lack of selective overexpression of β-III tubulin. This is a hypothesis generating study and additional analysis needs to be conducted from other large taxane-based trials.Partial support from Genentech and the Breast Cancer Research Foundation Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2100.

Abstract Background: Adenoid cystic carcinoma of the breast is a rare type of breast cancer accounting for approximately 0.1% of all breast cancer and less than 200 cases are reported in the literature. Hence, data for treatment and outcome are limited. This retrospective review reports the Mayo Clinic's experience.Methods: We identified 30 patients between 1971 and 2009 who were diagnosed with adenoid cystic breast cancer at Mayo Clinic Rochester, Arizona or Florida. Median follow-up was 62 months with a range of 1 to 424 months. Data regarding demographics (age, gender, and race), tumor characteristics (size, grade, and margin status), biological features (Estrogen receptor (ER), Progesterone receptor (PR) status, HER2 status) and clinical course (recurrence, secondary treatment) were collected. Disease free survival was calculated using Kaplan Meier estimates.Results: The median age of all patients was 58 (range, 22 – 78 years). All were female. Median tumor size was 1.3 cm (range, 0.6 – 8.5cm). Axillary lymph node sampling (sentinel or complete dissection) was performed in 15 patients. No patient had lymph node positive disease on presentation. The majority of patients had hormone receptor negative disease. Only 3 patients (10%) had weak hormone receptor (1-10%) positivity. No tumors were HER2 positive. Only two patients had high grade disease. Initial surgical data only available in twenty one patients: fifteen (50%) were treated with lumpectomy and adjuvant radiation, and 6 (20%) were treated with mastectomy. There were no local recurrences. Only one patient was treated with adjuvant chemotherapy (with cyclophosphamide, methotrexate and fluorouracil (CMF) followed by tamoxifen) but still suffered a distant recurrence within 5 years. There were a total of five patients that recurred. The 5-year disease free survival (DFS) rate for the entire cohort was 90%, and 10 year DFS was 83%. Median time to recurrence was 47.5 months (Range, 23-77 months). Recurrence occurred almost exclusively in patients with ≥ T2 disease. The primary site of metastases was lung (80%) and bone (20%) but subsequent liver and brain metastases were also seen. Treatments at relapse included surgical resection, radiosurgery and chemotherapy.Conclusion: Adenoid cystic carcinomas of the breast are rare but have overall good prognosis. This review confirms that the majority of these patients present with node negative disease, low to intermediate histologic grade and endocrine unresponsive tumors. Primary treatment is surgery (mastectomy or lumpectomy plus radiation) and there seems to be no role of any adjuvant therapy at the present time. In general, recurrences (80%) occurred with tumors larger than 2 cm and adjuvant chemotherapy and/or targeted therapy could be explored for selected patients in the context of a clinical trial. Overall mortality after recurrence was 50% but median overall survival was variable in years (1-14 years). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2055.

Abstract Abstract #6074 Objective: To analyze blood-serum biomarkers (HER2, EGFR, uPA, and TIMP-1) for prediction of response to treatment in conjunction with Study 96-32-55, a multicenter phase II trial assessing the efficacy and tolerability of two irinotecan schedules in anthracycline- or taxane-refractory MBC patients.&#x2028; Methods: MBC patients who experienced disease progression after one to three chemotherapy regimens, including at least one anthracycline- or taxane-based regimen, were randomly assigned to irinotecan in 6-week cycles comprising 100 mg/m2 weekly for 4 weeks, then a 2-week rest or 240 mg/m2 every 3 weeks. During this study the serum samples from each patient were collected at a possibility of three time points; prior to treatment, at the first occurrence of response, and at completion of or withdrawal from treatment. Response prediction was analyzed using predetermined elevated/non-elevated serum biomarker cutoffs. Percentage changes from baseline to first response and disease progression were analyzed.&#x2028; Results: In the weekly arm, the objective response (CR+PR) rate was 23% (95% CI, 13% to 37%), and in the every-3-weeks arm, the objective response rate was 14% (95% CI, 6% to 26%). Serum biomarker levels were determined for HER2, EGFR, uPA, and TIMP-1 prior to treatment for 91 patients. Of these 91 patients, 17 had serum measurements at first response, and 38 had serum measurements at their completion of study due to disease progression. Only 7 patients had serum-levels collected at all three event-points. The baseline levels of sHER2, EGFR, uPA, and TIMP-1 were not different among responders and non-responders (Fisher's Exact p=0.41, 0.26, 0.68, 0.75). sHER2 level increased by 20.6% from baseline to disease progression (p=0.01). TIMP-1 level was 15.2% lower than baseline at first response (p=0.03), 16.5% higher than baseline at disease progression (p=0.01), and for 7 patients with all three event-point measures, TIMP-1 was 21.8% lower than baseline at first response and was 22.3% higher than baseline at disease progression (p=0.02, 0.04).&#x2028; Conclusions: In this study, serum levels of HER2, EGFR, uPA, and TIMP-1 do not appear to be predictive of response. However, interpretation of the data is compromised due to limited availability of serum at all 3 points. Serum HER2 appears higher at disease progression than at baseline. Serum TIMP-1 appears to decrease from baseline to first response, and then appears to increase at disease progression. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6074.

Purpose We conducted a cooperative group phase II study to assess antitumor activity and toxicity of sorafenib in patients with metastatic breast cancer (MBC) who had received prior treatment for their disease. Patient and Methods Patients were eligible if they had measurable disease and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. The primary end point of the study was tumor response per Response Evaluation Criteria in Solid Tumors (RECIST). The study was designed in two stages. Sorafenib was administered as 400 mg twice daily on days 1 through 28 of each 4-week cycle. Results Twenty-three patients were enrolled with a median age of 54 years (range, 37 to 70 years). Twenty-two (96%) had prior anthracycline treatment and 16 (70%) had prior taxane treatment. Patients received sorafenib for a median of two cycles (range, one to 15 cycles) with a median follow-up of 2.4 years (range, 2.2 to 2.6 years). There were no grade 4 toxicities and few grade 3 toxicities. Among the 20 patients eligible for efficacy analysis, no patients experienced a partial response or complete response per RECIST criteria. Thus, the trial stopped at the end of the first stage per study design. Two patients (10%; 90% CI, 1.8% to 28.3%) achieved stable disease lasting longer than 6 months. Conclusion Sorafenib as a single agent, although well tolerated, did not exhibit activity when measured by tumor shrinkage in patients with MBC who had received prior treatment. Further research should focus on combinations with standard therapy and end points more sensitive to effects of targeted agents, such as disease stabilization.