Beth A. Hellerstedt

Gene Pathways Associated With Prognosis and Chemotherapy Sensitivity in Molecular Subtypes of Breast Cancer

BACKGROUND We hypothesized that distinct biological processes might be associated with prognosis and chemotherapy sensitivity in the different types of breast cancers. METHODS We performed gene set analyses with BRB-ArrayTools statistical software including 2331 functionally annotated gene sets (ie, lists of genes that correspond to a particular biological pathway or biochemical function) assembled from Ingenuity Pathway Analysis and Gene Ontology databases corresponding to almost all known biological processes. Gene set analysis was performed on gene expression data from three cohorts of 234, 170, and 175 patients with HER2-normal lymph node-negative breast cancer who received no systemic adjuvant therapy to identify gene sets associated prognosis and three additional cohorts of 198, 85, and 62 patients with HER2-normal stage I-III breast cancer who received preoperative chemotherapy to identify gene sets associated with pathological complete response to therapy. These analyses were performed separately for estrogen receptor (ER)-positive and ER-negative breast cancers. Interaction between gene sets and survival and treatment response by breast cancer subtype was assessed in individual datasets and also in pooled datasets. Statistical significance was estimated with permutation test. All statistical tests were two-sided. RESULTS For ER-positive cancers, from 370 to 434 gene sets were associated with prognosis (P ≤ .05) and from 209 to 267 gene sets were associated with chemotherapy response in analysis by individual dataset. For ER-positive cancers, 131 gene sets were associated with prognosis and 69 were associated with pathological complete response (P ≤.001) in pooled analysis. Increased expression of cell cycle-related gene sets was associated with poor prognosis, and B-cell immunity-related gene sets were associated with good prognosis. For ER-negative cancers, from 175 to 288 gene sets were associated with prognosis and from 212 to 285 gene sets were associated with chemotherapy response. In pooled analyses of ER-negative cancers, 14 gene sets were associated with prognosis and 23 were associated with response. Gene sets involved in sphingolipid and glycolipid metabolism were associated with better prognosis and those involved in base excision repair, cell aging, and spindle microtubule regulation were associated with chemotherapy response. CONCLUSION Different biological processes were associated with prognosis and chemotherapy response in ER-positive and ER-negative breast cancers.

Phase III Study of Iniparib Plus Gemcitabine and Carboplatin Versus Gemcitabine and Carboplatin in Patients With Metastatic Triple-Negative Breast Cancer

PURPOSE There is a lack of treatments providing survival benefit for patients with metastatic triple-negative breast cancer (mTNBC), with no standard of care. A randomized phase II trial showed significant benefit for gemcitabine, carboplatin, and iniparib (GCI) over gemcitabine and carboplatin (GC) in clinical benefit rate, response rate, progression-free survival (PFS), and overall survival (OS). Here, we formally compare the efficacy of these regimens in a phase III trial. PATIENTS AND METHODS Patients with stage IV/locally recurrent TNBC who had received no more than two previous chemotherapy regimens for mTNBC were randomly allocated to gemcitabine 1,000 mg/m(2) and carboplatin area under the curve 2 (days 1 and 8) alone or GC plus iniparib 5.6 mg/kg (days 1, 4, 8, and 11) every 3 weeks. Random assignment was stratified by the number of prior chemotherapies. The coprimary end points were OS and PFS. Patients receiving GC could cross over to iniparib on progression. RESULTS Five hundred nineteen patients were randomly assigned (261 GCI; 258 GC). In the primary analysis, no statistically significant difference was observed for OS (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12; P = .28) nor PFS (HR = 0.79; 95% CI, 0.65 to 0.98; P = .027). An exploratory analysis showed that patients in the second-/third-line had improved OS (HR = 0.65; 95% CI, 0.46 to 0.91) and PFS (HR = 0.68; 95% CI, 0.50 to 0.92) with GCI. The safety profile for GCI was similar to GC. CONCLUSION The trial did not meet the prespecified criteria for the coprimary end points of PFS and OS in the ITT population. The potential benefit with iniparib observed in second-/third-line subgroup warrants further evaluation.

Gemcitabine, cisplatin, and sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscle-invasive bladder cancer

BACKGROUND Data support chemotherapy combined with antiangiogenic therapy in metastatic urothelial cancer (mUC) and muscle-invasive bladder cancer (MIBC). We investigated the efficacy and safety of gemcitabine, cisplatin, and sunitinib (GCS) in mUC and MIBC in parallel phase II trials. PATIENTS AND METHODS Trial 1 enrolled 36 patients with mUC who were chemotherapy naive; trial 2 enrolled 9 patients with MIBC. The primary endpoints for trials 1 and 2 were response rate and pathologic complete response, respectively. GCS was given as first-line treatment for patients with mUC and as neoadjuvant therapy for patients with MIBC. The Simon minimax 2-stage design was used for an objective response rate in trial 1 and for the pathologic complete response rate in trial 2. RESULTS The initial trial 1 GCS dose was gemcitabine 1000 mg/m(2) intravenously, days 1 and 8; cisplatin 70 mg/m(2) intravenously, day 1; and sunitinib 37.5 mg orally daily, days 1 to 14 of a 21-day cycle. These doses proved intolerable. The doses of gemcitabine and cisplatin were subsequently reduced to 800 and 60 mg/m(2), respectively, without an improvement in drug delivery, and the trial was closed. This lower-dose regimen was applied in trial 2, which was stopped early due to excess toxicity. Grade 3 to 4 hematologic toxicities occurred in 70% (23/33) of patients in trial 1 and 22% (2/9) of patients in trial 2. In trial 1, the response rate was 49% (95% CI, 31%-67%); in trial 2, the pathologic complete response was 22% (2/9). Due to early closure secondary to toxicity, the sample sizes of both trials were small. CONCLUSIONS Delivery of GCS was hampered by excessive toxicity in both advanced and neoadjuvant settings.

Administration of cisplatin-based chemotherapy for advanced urothelial carcinoma in the community.

BACKGROUND Renal dysfunction, poor performance status, and comorbidities may preclude frontline cisplatin-based chemotherapy in patients with advanced urothelial carcinoma (UC). The frequency of cisplatin-based chemotherapy administration in patients with advanced UC in community-based cancer centers is unknown. PATIENTS AND METHODS A retrospective study was conducted to evaluate chemotherapy regimens administered to patients with the AJCC (American Joint Committee on Cancer) stage-4 UC who, from 2001 to 2010, presented to Texas Oncology Cancer Centers. Frontline chemotherapy was classified as cisplatin based, carboplatin based, nonplatinum based, and as no chemotherapy administered. RESULTS A total of 298 patients were eligible for analysis, of whom 197 (66.1%) were men. The median age was 70 years (range, 28-97 years), and the primary sites of disease were bladder (243 [81.5%]), renal pelvis (41 [13.8%]), and ureter (14 [4.7%]). Overall, the regimens administered were cisplatin based in 107 patients (35.9%), carboplatin based in 81 (27.2%), and nonplatinum based in 25 (8.4%); no chemotherapy was administered in 71 (23.8%), and data were not available in 14 patients (4.7%). Cisplatin administration was more common in patients aged ≤70 years (62/150 [41.3%]) as opposed to >70 years (45/148 [30.4%]) (P = .05). Noncisplatin regimens or no chemotherapy were trending to be more commonly administered to patients >70 years (64.2 vs. 54.7%; P = .10). Limitations of a retrospective database study apply. CONCLUSION A first-line cisplatin-based regimen was administered to 35.9% of patients who presented with AJCC stage 4 UC in a community-based cancer center network. Drug development focused on tolerable single-agent therapy or combination regimens without a cisplatin backbone should be a priority.

Phase II study of gemcitabine, cisplatin, and sunitinib in patients with advanced urothelial carcinoma (UC).

282 Background: Sunitinib (S) has single-agent activity in patients with advanced urothelial carcinoma (UC). Preclinical studies in UC demonstrate at least additive antitumor activity combining S with gemcitabine (G) or cisplatin (C). METHODS Patients with chemonaïve metastatic UC were enrolled in a multicenter phase II trial with overall response rate (ORR) as the primary endpoint. The initial dosing regimen, based on a phase I trial (Reck, 2010), was G 1000 mg/m2 IV (Days 1 & 8), C 70 mg/m2 IV (Day 1), and S 37.5 mg PO daily (Days 1-14)/each 21-day cycle (up to 6 cycles), followed by S 37.5 mg daily until progression. RESULTS From December 2008 to August 2009, 15 eligible patients enrolled. Seven of 15 patients discontinued treatment early (median: 3 cycles) due to toxicity, most often due to recurrent neutropenia and thrombocytopenia. Intrapatient dose reductions were required for G (12/15), C (8/15), and S (10/15). Eight of 15 patients experienced serious adverse events. Based on the toxicity profile, enrollment was held and the dosing regimen was revised to G 800 mg/m2 IV (Days 1 and 8), C 60 mg/m2 IV (Day 1), S 37.5 mg PO daily (Days 1-14). From December 2009 to April 2011, 18 additional patients were enrolled. Despite the reduced starting doses, intrapatient dose reductions were required for G (13/18), C (9/18), and S (15/18). The most frequent Grade 3-4 toxicities for both groups were neutropenia (70%), thrombocytopenia (58%), and anemia (30%). Antitumor activity is shown in the Table. Median PFS was 7.9 and median OS was 13.8 months. CONCLUSIONS Combination G+C+S is poorly tolerated and results in activity comparable to historical results with G+C alone. Supported in part by a grant from Pfizer Inc. [Table: see text].

Incidence and Predictive Factors for Recovery of Ovarian Function in Amenorrheic Women in Their 40s Treated With Letrozole

PURPOSE This prospective study assessed the impact of 2 years of aromatase inhibitor (AI) therapy on the incidence of ovarian function recovery (OFR) in women age 40 to 49 with estrogen receptor-positive breast cancer who were premenopausal at diagnosis and who underwent chemotherapy-induced amenorrhea during adjuvant treatment. PATIENTS AND METHODS Women age 40 to 49 with estrogen receptor-positive breast cancer who had ceased menstruating with adjuvant cyclophosphamide-based chemotherapy, had postmenopausal serum estradiol (E2), and had received tamoxifen for ≥ 1 year were treated with letrozole (2.5 mg) daily for ≥ 2 years. Serum follicle-stimulating hormone (FSH) and E2 were measured at baseline and over 2 years. A general linear model was used to assess serial FSH by OFR. Logistic regression was used to assess baseline predictors and OFR. RESULTS The study enrolled 177 women (145 women age 45 to 49 years and 32 women age 40 to 44 years). Of 173 evaluable patients, 67 (39%; 95% CI, 31% to 46%) regained ovarian function; 11 of these patients (6%; 95% CI, 3% to 10%) resumed menses, and 56 of these patients (32%; 95% CI, 25% to 39%) developed premenopausal E2 without menses. Among AI-naïve patients, serial FSH significantly increased over time (P < .001), did not vary significantly by OFR status (P = .55), but showed mild evidence of a decrease after month 12 for those who resumed menses (P = .0989). Age less than 45 years and inhibin B were significant multivariable baseline predictors of OFR. CONCLUSION These results emphasize the challenge in determining definitive menopause in women with chemotherapy-induced amenorrhea. The risk of OFR during treatment with AIs in amenorrheic women in their 40s is high, and AI therapy should be avoided in these patients.

Postsplenectomy cytomegalovirus mononucleosis is a distinct clinicopathologic syndrome.

Lymphocytosis in response to viral infection, such as infectious mononucleosis, rarely exceeds 20 x 10(9)/L in the adult population. Transfusion-acquired cytomegalovirus (CMV) mononucleosis after trauma-related splenectomy may cause prominent lymphocytosis, but the history and timing usually hint at the diagnosis. We describe a case of severe CMV mononucleosis that was acquired naturally decades after splenectomy. Together with the 2 similar cases that we reported recently, these cases all presented as initial diagnostic challenge because of a remote history of splenectomy, a prolonged febrile illness (approximately 4 weeks), marked lymphocytosis (peak 27.9 x 10(9)/L), and undetectable or weakened anti-CMV IgM antibody response. The diagnosis was eventually established through detection of circulating CMV antigen or DNA and a year or longer follow-up with serial determination of IgM and IgG antibodies. Two similar cases were also identified in the literature and reviewed. Although the impaired IgM response may confuse the diagnosis, it correlates well with recent studies showing that human blood IgM memory B cells are circulating splenic marginal zone B cells; asplenic or splenectomized individuals, irrespective of the underlying cause, have undetectable IgM memory B cells. Together, these findings suggest that distant or recent postsplenectomy CMV mononucleosis represents a distinct clinicopathologic syndrome resulting from poor control of early viremia because of the lack of both splenic filtration and the typical brisk IgM response. For the practicing clinician, recognizing these features may aid timely diagnosis and treatment.

Frequency of cisplatin administration in patients presenting with advanced urothelial carcinoma in the community.

285 Background: Renal dysfunction, poor performance status, advanced age, and comorbidities may preclude standard frontline cisplatin-based chemotherapy in patients with advanced urothelial carcinoma (UC). We hypothesized that cisplatin-based regimens are not administered to the majority of patients in the community. A study was conducted to identify chemotherapy regimens administered by medical oncologists in community-based cancer centers. METHODS A retrospective study was conducted on patients with AJCC stage 4 UC presenting from 2001 to 2010 to Texas Oncology Cancer Centers. The frontline chemotherapy regimen was classified as cisplatin-based, carboplatin-based, non-platinum based and no chemotherapy administered. The association of age with administration of cisplatin was studied. RESULTS A total of 298 patients with stage 4 disease were eligible for this analysis out of 3574 patients with UC in this database. Of the 298 patients, 197 (66.1%) were male, the median age was 70 years (range 28-97), and the primary sites of disease were bladder (243, 81.5%), renal pelvis (41, 13.8%) and ureter (14, 4.7%). The regimens administered were cisplatin-based in 107 patients (35.9%), carboplatin-based in 81 (27.2%), non-platinum in 25 (8.4%), no chemotherapy was administered in 71 (23.8%) and data were not available in 14 patients (4.7%). Cisplatin administration appeared more common in patients aged ≤70 years (62 of 150, 41.3%) as opposed to >70 years (45 of 148, 30.4%), p=0.05. Non-cisplatin regimens or no chemotherapy were trending to be more commonly administered to patients >70 years (64.2 vs. 54.7%, p=0.10). Limitations of a retrospective database study apply and the reasons for not administering cisplatin are unclear. CONCLUSIONS Cisplatin-based chemotherapy was administered to 35.9% of patients presenting with AJCC stage 4 UC to community cancer centers. Given that the majority of patients may not be cisplatin-eligible or candidates for chemotherapy, this population has a significant unmet need. Drug development focused on single agent therapy with tolerable, convenient and efficacious agents or combination regimens without a cisplatin backbone should be a priority.

Results of a Phase 2 Placebo-Controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non–Small-Cell Lung Carcinoma

Introduction: Cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against MET, vascular endothelial growth factor receptor 2, AXL, ROS1, and RET was assessed in patients with non–small‐cell lung carcinoma (NSCLC) as part of a phase II randomized discontinuation trial with cohorts from 9 tumor types. Patients and Methods: Patients received cabozantinib 100 mg/day during a 12‐week open‐label lead‐in stage. Those with stable disease per Response Evaluation Criteria in Solid Tumors version 1.0 at week 12 were randomized to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and progression‐free survival (PFS) after randomization. Results: Sixty patients with NSCLC who had received a median of 2 prior lines of therapy were enrolled. ORR at week 12 was 10%; 6 patients had a confirmed partial response, and no patients had a complete response. Overall disease‐control rate (ORR + stable disease) at week 12 was 38%. Tumor regression was observed in 30 (64%) of 47 patients with post‐baseline radiographic tumor assessments, including 3 or 4 patients with KRAS or epidermal growth factor receptor mutations, respectively. Median PFS after randomization was 2.4 months for both the cabozantinib and placebo arms. Median PFS from first dose for the entire cohort was 4.2 months. The most common grade 3/4 adverse events were fatigue (13%), palmar‐plantar erythrodysesthesia (10%), diarrhea (7%), hypertension (7%), and asthenia (5%); 1 treatment‐related grade 5 adverse event (hemorrhage) was reported during the lead‐in stage. Conclusion: Cabozantinib exhibited clinical activity based on ORR and regression of tumor lesions in pretreated patients with NSCLC, including in patients with KRAS mutations. Micro‐Abstract: Cabozantinib is an inhibitor of receptor tyrosine kinases, including MET, vascular endothelial growth factor receptors, AXL, RET, and ROS1. We assessed cabozantinib in 60 patients with non–small‐cell lung carcinoma enrolled in a phase II randomized discontinuation trial. Tumor regression was observed in most patients, including patients with KRAS and epidermal growth factor receptor mutations. The safety profile was consistent with that reported for cabozantinib in other solid tumors.

Five-year results of a phase II trial of preoperative 5-fluorouracil, epirubicin, cyclophosphamide followed by docetaxel with capecitabine (wTX) (with trastuzumab in HER2-positive patients) for patients with stage II or III breast cancer

We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5‐fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2‐positive disease) and to evaluate 5‐year disease‐free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5‐fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 IV on Day 1 every 21 days) followed by 4 21‐day cycles of docetaxel (35 mg/m2 days 1 and 8) concurrently with capecitabine (825 mg/m2 orally twice daily for 14 days followed by 7 days off) (wTX). For HER2‐positive patients, treatment was modified by decreasing epirubicin to 75 mg/m2 and adding trastuzumab (H) in standard doses (FEC75‐H →wTX‐H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2‐negative breast cancer and of 67% in patients with HER2‐positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent‐to‐treat analysis, the pCR rate was 31% (37/118, 95% CI: 24–40%) in the HER2‐negative patients, 24% (15/62, 95% CI: 14–37%) in ER‐positive/HER2‐negative patients, 39% (22/56, 95% CI: 27–53%) in the ER‐negative/HER2‐negative patients, and 46% (29/63, 95% CI: 34–48%) in the HER2‐positive patients. The pCR rate in the 40 trastuzumab‐treated patients was 53% (21/40, 95% CI: 38–67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand‐foot skin reactions. One trastuzumab‐treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1–2 decrements in left ventricular function; all five patients’ cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease‐free survival was 70% in the HER2‐negative population (78% in ER‐positive/HER2‐negative and 62% in the ER‐negative/HER2‐negative patients) and 80% in the HER2‐positive patients (87% in the trastuzumab‐treated HER2‐positive patients). At 5 years, overall survival was 80% in the HER2‐negative population (88% in ER‐positive/HER2‐negative and 71% in the ER‐negative/HER2‐negative patients) and 86% in the HER2‐positive patients (94.5% in the trastuzumab‐treated HER2‐positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5‐year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended.