Abstract Purpose: Statins may mediate suppression of molecular pathways conferring benefit in cancer. Statins have shown anti-tumor effects in preclinical studies and have been associated with decreased recurrence and improved disease-specific survival. While designed to target cholesterol biosynthesis, statins can also have liver, bone and brain effects. We collected data on statin use in the S0307 adjuvant bisphosphonate trial to test the hypothesis that statin use may decrease risk of recurrence to liver, bone and brain as well as second primary (contralateral) breast cancers, and may act synergistically with bisphosphonates to decrease the risk of recurrence to bone. Patients and Methods: In S0307, 6097 patients diagnosed with Stage I-III breast cancer who had undergone surgery and were receiving adjuvant systemic therapy were randomized to receive zoledronic acid, clodronate, or ibandronate for 3 years. No significant difference was found in disease-free survival (DFS) among the 3 groups, including a sub-analysis of patients > age 55. Statin use was infrequent in younger women in S0307, consequently we analyzed statin use in those > age 55. Cox proportional hazard models were used to determine which variables were independently associated with DFS and to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: Among women aged ≥ 55 years, 684 (27%) reported taking a statin at baseline and 1,848 did not. Both groups were similar in terms of hormone receptor and HER2 status (p = 0.82). Median age in the statin group was 64.3 versus 61.0 years in the no statin group, mean BMI 31.2 v. 29.5, mean tumor size 2.1cm v. 2.3cm, negative lymph nodes 60% v. 54%, Stage I disease 47% v. 36%, and receipt of chemotherapy 62% v. 71% (all p < 0.01). In the statin group, 122 (17.8%) experienced a DFS event compared to 313 (16.9%) in the no statin group (HR 1.18, CI 0.95-1.46). No difference was observed by statin use in overall recurrence (p=0.28), distant recurrence (p=0.64), or recurrences to the bone (p=0.64), liver (p=0.38) or brain (p=0.65) at initial recurrence. There was no synergy between statin use and specific bisphosphonates. Recurrence and statin useOutcomeGroup 1: On stan at baseline n=684Group 2: No statin at baseline n=1848DFS events122 (17.8%)313 (16.9%)Died without recurrence51 7.5%)97 (5.2%)Recurrence71 (10.4%)216 (11.7%)Contralateral breast cancer9 (1.3%)17 (0.9%)Distant recurrence48 (7%)157 (8.5%)Bone as 1st site of distant recurrence (% distant recurrence)31 (65%)76 (48%)Liver as 1st site of distant recurrence (% distant recurrence)6 (13%)24 (16%)Brain/CNS as 1st site of distant recurrence (% distant recurrence)5 (10%)17 (11%) Conclusions: We found no evidence that statins reduce risk of second primary breast cancers or distant metastases among post-menopausal women with early-stage breast cancer. Despite promising preclinical data, they did not appear to act in synergy with a specific bisphosphonate. Though women in the statin group had less advanced disease at study entry, statin use was not associated with improved DFS. Results are limited by lack of information about type of statin used, adherence, or initiation of statin in control group. Citation Format: Kizub D, Miao J, Stopeck A, Thompson P, Paterson AH, Clemons M, Dees EC, Ingle JN, Falkson CI, Barlow W, Hortobagyi GN, Gralow JR. Statin use, site of recurrence, and survival among post-menopausal women taking bisphosphonates as adjuvant therapy for breast cancer (SWOG S0307) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-03.

Abstract Hypothesis: Pharmacologic inhibition of angiogenesis and mTOR pathway blockade will enhance the efficacy of aromatase inhibitors in the neoadjuvant setting in women with hormone receptor-positive and Her2-negative (HR+/Her2-) breast cancer. Background: In non-metastatic HR+/Her2- breast cancer, downstaging to stage I or 0 in the neoadjuvant setting has been associated with favorable prognosis. With chemotherapy yielding similar benefits with endocrine therapy, aromatase inhibitors have become the agents of choice in postmenopausal women. The elucidation of pathways that are operational in luminal breast cancer and compromise the efficacy of hormonal therapy along with preclinical and clinical evidence of successful combinations of endocrine therapy with targeted agents set the stage for more rational, effective, and equally well tolerated regimens. Proangiogenic signaling has been strongly associated with accelerated hormone-independent growth and resistance to endocrine therapies. Breast cancer cells with upregulated PI3K/AKT/mTOR pathway are resistant to hormonal therapy and this resistance has been restored by everolimus. Inhibiting mTOR, a downstream signaling node where multiple pathways converge has the potential to abrogate primary and escape signaling cascades that mediate resistance to endocrine therapies. Study Design: Phase I dose escalation: follows a 3+3 design. During the phase I, the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) will be determined. Letrozole will be kept the same for all cohorts (2.5 mg PO qd). Everolimus will be escalated from 5 mg (cohort 1) to 10 mg PO qd (cohort 2). TRC105 will be 15 mg/kg q2 weeks (cohorts 1 and 2). Premenopausal women at the time of enrollment will receive goserelin 3.6 mg SC q4 weeks to achieve ovarian suppression. Duration of treatment is 24 weeks. Phase II dose expansion: will be initiated once the MTD and RP2D have been determined. Phase II follows a Gehan's two-stage design: 10 patients will enroll first, and if no patient has achieved downstaging, the study will close since it is unlikely (p=0.1) that 0/10 responses would occur if true response rate were >20%. If at least one patient has downstaging, 10 additional patients will enroll (total, 20). Primary Objectives Phase I: Determine the tolerability and feasibility of letrozole, everolimus, and TRC105 in women with newly diagnosed stage 2 and 3 HR+/Her2- breast cancer. Phase II: in the same patient population determine the efficacy, pharmacokinetic, and pharmacodynamic parameters of the combination. Correlative Studies: Immunohistochemistry for pAKT and PTEN, CD105, CD31/CD34, NG2, MCAM/CD146 on diagnostic tissue, research biopsy, and final surgical specimen. Surgical specimens that meet criteria for next-generation sequencing will undergo ribosome profiling Key Eligibility Criteria: Recent diagnosis of HR+Her2- breast cancer Stage 2 and 3 breast cancer Any histological grade No prior treatment specific for breast cancer Pre- and perimenopausal women are eligible if ovarian suppression is achieved with goserelin. Current Status: Cohort 1 of the Phase 1 complete. Cohort 2 of Phase 1 actively enrolling. Citation Format: Vaklavas C, Lamaster KV, Stringer EM, Falkson CI, Li Y, Forero A. A phase I/II study of preoperative letrozole, everolimus, and TRC105 in women with newly diagnosed local or locally advanced potentially resectable hormone-Receptor positive and Her2 negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-06-06.

Abstract Background: Triple negative breast cancer (TNBC) comprises 15–20% of newly diagnosed invasive breast cancers and has been associated with an elevated risk of both local-regional recurrence (LRR) as well as distant failure. Bevacizumab (BEV) has been shown to improve pathologic complete response rates in the setting of neoadjuvant chemotherapy (NCT), but its effect on LRR remains undefined. This study reports the impact of adding BEV to standard breast cancer therapy in TNBC patients treated at a single institution. Methods: One hundred and eighty-five consecutive TNBC patients treated at the University of Alabama Birmingham from May 2005 to August 2010 were reviewed. Thirty-one TNBC patients treated with chemotherapy (CT) and BEV on prospective studies were matched (1:2) with 62 TNBC patients treated with CT alone, controlling for age, stage, and use of radiation (RT). The Kaplan-Meier method was used to estimate LRR, distant metastasis-free survival (DMFS), and overall survival (OS), and cohorts were compared using Cox proportional hazards models and the 2-sided log-rank test. Results: Mean age was 47 and 46 years in the cohorts with and without BEV, respectively. Stage in each cohort was as follows: 32% stage I, 61% stage II, and 7% stage III. Use of adjuvant RT was 81% in each cohort (25/31 BEV, 50/62 no BEV). BEV was delivered with NCT in 17 patients (55%) and with adjuvant CT in the remaining 14 patients (45%). Eleven patients (35%) completed an additional 1 year of maintenance therapy with BEV. LRR occurred in 2 (6%) patients treated with BEV vs. 16 (26%) treated with CT alone (HR = 0.25, 95% CI 0.06–1.07, p = 0.04). Distant recurrence occurred in 3 (10%) patients treated with BEV vs. 11 (18%) patients in the CT group HR=0.6, 95% CI 0.2–1.8, p = 0.48). There were 2 (6%) deaths in the BEV group vs. 12 (19%) in the CT alone group (HR = 0.55, 95% CI 0.13–2.3, p = 0.19). Conclusions: In a matched-pair analysis of TNBC patients, the addition of BEV to conventional breast cancer management was associated with a reduction in LRR. Further prospective study is necessary to examine the impact of BEV on local-regional control in TNBC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-07.

Abstract Background We evaluated the safety and efficacy of L+T in pts with 0–2 prior lines of chemotherapy (CT) for HER2+ MBC. In the context of this phase II trial, we evaluated metabolic response by FDG-PET and explored the relationship between metabolic response and clinical outcomes. Methods: Pts with measurable, HER2+ MBC were eligible. Cohort 1: No prior T, L, or CT +T for MBC, and >1 yr from adjuvant T, if received. Cohort 2: 1–2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). Staging studies were done with CT or MRI at baseline (BL) and every 2 cycles (1 cycle=4 weeks [wks]). Objective response was assessed by local investigator according to RECIST 1.0. FDG-PET/CT was performed at BL, Wk 1, and Wk 8 per NCI guidelines. Central quality assurance, review, and analysis were performed on FDG-PET studies. Up to 5 target lesions were identified on BL FDG-PET images based on hypermetabolic uptake. Percent change in the summed maximum standardized uptake value (SUVmax) of target lesions was calculated at Wk 1 or Wk 8, compared to BL. Metabolic response was assessed according to EORTC criteria for % change in SUVmax (progressive disease [PD]: ≥25% increase; partial response [PR]: ≥25% decrease; stable disease [SD]: <25% change). Metabolic response at Wk 1 was compared to Wk 8 as well as to clinical outcome, including objective response, clinical benefit, and progression-free survival (PFS). Results: 87 pts were registered to the study. Of these, one pt did not begin protocol therapy and one pt did not have MBC on further testing, and are not included. 81/85 pts had FDG-PET data at Wk 1; 75/85 had data at Wk 8. Metabolic PR at Wk 1 was observed in 28/39 (72%) pts in Cohort 1 and 20/42 (48%) pts in Cohort 2. Metabolic PR at Wk 8 was observed in 27/34 (79%) pts in Cohort 1 and 18/41 (44%) pts in Cohort 2. Wk 1 and Wk 8 metabolic responses were similar. In cohort 1, 18/28 (64%) pts who achieved Wk 1 metabolic PR had clinical benefit by RECIST. Of pts with Wk 1 metabolic SD, 2/9 (22%) had clinical benefit. In cohort 2, 9/20 (45%) pts who achieved Wk 1 metabolic PR had clinical benefit; 5/22 (23%) who achieved Week 1 metabolic SD had clinical benefit. Exploratory analysis of progression-free survival (PFS) showed that pts in Cohort 1 who achieved Wk 1 metabolic PR experienced a median PFS of 9.3 months ([mos]; 95% CI 5.6−22.3); for pts with metabolic SD, median PFS was 1.9 mos (95% CI 0.8−5.5). For pts in Cohort 2, Wk 1 metabolic PR was associated with median PFS of 5.6 mos (95% CI 3.7−7.8), whereas for pts with metabolic SD, median PFS was 3.7 mos (95% CI 1.8−5.5). Conclusions: L+T is associated with a high rate of early and sustained metabolic response by FDG-PET. Exploratory analyses suggest that metabolic PR may be associated with clinical benefit and longer PFS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-07.

Abstract We studied patients with locally advanced breast cancer (LABC) to evaluate 1) whether adding concurrent bevacizumab to preoperative chemotherapy (CT) would increase the pathologic complete response (pCR) rate, 2) whether a prolonged postoperative course of bevacizumab would prevent or reduce the recurrence rate in patients who did experience pCR after preoperative chemotherapy, and 3) whether use of pegylated liposomal doxorubicin would prove comparably effective to doxorubicin with less toxicity in this setting. From 3/08-12/09 32 patients with HER-2 negative operable (LABC) received sequential preoperative CT with pegylated liposomal doxorubicin 25 mg/M2 every 2 weeks X 3, paclitaxel 175 mg/M2 every 2 weeks X 3, and cyclophosphamide 60 mg/M2 every 2 weeks X 3, all with concurrent bevacizumab 10 mg/kg every 2 weeks. One patient's disease progressed by the end of CT; 1 patient withdrew after 2 cycles of treatment. All 30 remaining patients had ≥30% shrinkage of tumor at the completion of CT. Left ventricular ejection fractions on the 31 who completed CT were >55% before and after completing CT; no cardiac failure was seen. Grade III toxicities included hypertension >150/90 in 7 and palmar-plantar erythrodysesthesia in 1; other toxicities were grade I or II. No proteinuria was seen. Five experienced delayed wound healing after operation. Responses: 9/32 pCR in breast and axillary nodes (2/15 in ER or PR+, 7/17 in ER/PR-), and 3 pCR in breast with ≥1 positive axillary node (2 ER or PR+, 1 ER/PR-). Hormonal treatment but no further CT was given after operation. 20/21 patients with residual invasive cancer in breast or nodes started an additional year of bevacizumab 15 mg/kg every 3 weeks; 1 never started bevacizumab due to delayed wound healing- her disease recurred before starting bevacizumab and she died 22 months after diagnosis. All but 6 of these have completed the additional year of bevacizumab (1 withdrew early due to the need for 2 emergency abdominal operations); 1 experienced recurrence in lungs during bevacizumab treatment and subsequently died 24 months after starting treatment (ER+). An additional patient with initial pCR experienced recurrence in brain, then lung 18 months after starting treatment (ER/PR -). With a median followup of 26.5 months since diagnosis, 30 of 32 remain alive, 28 of 32 remain free of recurrence, and 19 of the 20 who started bevacizumab for less than pCR after operation remain free of recurrence. Concurrent bevacizumab did not appear to influence the pCR rate from preoperative CT. The pCR rate observed using pegylated liposomal doxorubicin is comparable to that obtained at UAB with sequential treatment using doxorubicin, but is less toxic. Use of bevacizumab after operation in patients with LABC who do not experience pCR from preoperative chemotherapy may decrease recurrence and appears promising. Further observation in this group and further prospective study will be of interest. Supported by Centocor Ortho Biotech Services and by Genentech Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-31.

Abstract Bisphosphonates reduce the incidence of skeletal-related events (fractures, pain, hypercalcemia) in patients (pts) with bone metastases from breast cancer. By inhibiting osteoclast function and subsequent bone turnover they may inhibit the growth of bone (and other) metastases. Their role in preventing or delaying the development of bone (or other) metastases in pts with early breast cancer is uncertain. Three previous trials of oral clodronate have given mixed results. The largest trial (placebo-controlled) and a smaller open-label trial suggested that oral clodronate benefitted pts with improved bone metastases-free survival (BMFS) and overall survival (OS), but a third open-label study showed no benefit with an apparent detrimental effect on survival. Studies of IV zoledronate in open-label trials in early breast cancer have also shown mixed results: the AZURE trial in pts with node positive breast cancer showed no benefit in disease-free survival (DFS) or OS with a possible effect in pts aged over 60. The ABCSG-12 trial in GnRH (plus tamoxifen or anastrozole) treated women with early breast cancer showed a small DFS benefit for those receiving IV zoledronate but no BMFS or OS benefit. Methods: B-34 is a prospective, randomized, double-blind, phase III clinical trial in pts with stage 1, 2 or 3 breast cancer assessing oral clodronate 1600mg daily for 3 years compared to placebo given alone or in addition to adjuvant chemo- or hormone therapy. Stratification is by age (<50, +50), number of positive nodes (0, 1–3, 4+) and ER/PR status. The primary end-point is DFS. Secondary endpoints are the incidence of skeletal metastases, OS, relapse-free survival, incidence of non-skeletal metastases, and incidence of skeletal morbid events. Results: 3323 patients were accrued — 1662 in Group A and 1661 in Group B. As of March 31, 2011, 54 pts were declared ineligible: 23 in Group A and 31 in Group B. The average time on study is 101.3 months. Patient characteristics were evenly distributed throughout both groups. Approximately 75% of pts in each group had negative axillary lymph nodes and some 78% in each group were ER and/or PR positive. About 64% of pts were age 50 or over. Oral clodronate was generally tolerable, toxicities observed being mainly due to the concomitant systemic chemotherapy. One pt in Group A had a 1 mm area of osteonecrosis on the palatal taurus. Compliance, as expected with trials of oral medications, has been a problem. 1910 pts completed 3 years of therapy. Event rates were slower than anticipated. This final analysis assesses a total of 598 events in the two arms. Conclusions: This trial is the largest placebo-controlled study of an oral bisphosphonate in patients with early breast cancer and will provide further information on the role of bisphosphonates in breast cancer management. Supported for NSABP by NCI U10CA12027, −37377, 69651, 69974; and Bayer Schering Pharma Oy; for ECOG by U10CA021115; for NCCTG by U10CA25224; for SWOG by U10CA38926. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-3.

Abstract From 3/08 through 12/09, 32 patients with HER-2 negative locally advanced breast cancer (LABC) received preoperative chemotherapy (CT) with sequential dose-dense chemotherapy consisting of pegylated liposomal doxorubicin 25 mg/M2 every 2 weeks X 3, paclitaxel 175 mg/M2 every 2 weeks X 3, then cyclophosphamide 600 mg/M2 every 2 weeks X 3, all with concurrent bevacizumab 10 mg/kg every 2 weeks. One patient had progression of disease during treatment and a second developed bone metastasis by the completion of CT. 30/32 had at least 30% shrinkage of tumor clinically. No patient developed cardiac failure. All 31 patients who completed CT had > 55% Left ventricular ejection fraction on echocardiogram before and after CT. The only toxicities greater than grade 2 were skin—grade 3 palmar plantar erythrodysesthesia in 1 and grade 3 hypertension with BP >150/90 in 7 patients. 12 doses of bevacizumab were held due to a blood pressure > 150/90. No proteinuria was seen. 5 patients experienced delayed wound healing after operation. 8/32 pathologic complete responses (pCR) were seen, 2/21 in ER and/or PR positive disease and 6/11 in ER and PR negative disease. 4 additional patients had no invasive tumor remaining in the breast but had ≥1 involved axillary node. Hormonal therapy but no further CT was given postoperatively. 20 patients who had residual invasive tumor and/or involved axillary nodes at operation will receive an additional year of Avastin 15 mg/kg every 3 weeks. 1 patient received only 2 doses, 13 have completed or are receiving bevacizumab, 6 patients have not yet started. None of these 20 has relapsed, with a median followup of 15 months (range 6 to 27 months). 1 who did not receive bevacizumab due to delayed wound healing had progression 6 months after CT. Concurrent bevacizumab with preoperative CT may not influence the rate of pCR; postoperative bevacizumab may decrease recurrence after operation in patients with LABC. Supported through grants from Centocor Ortho Biotech Services & from Genentech Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-24.

Background: This phase 11 trial was performed to assess the activity and safety of the cisplatin and vinorelbine combination in patients with advanced cervical carcinoma. Patients and Methods: Forty-two patients with advanced cervical cancer were included in the study to receive vinorelbine at 30 mg/m(2) on d 1 and d 8 and cisplatin 100 mg/m(2) on day 1 every 4 weeks. Results: Thirty-seven patients were evaluable for response and 40 patients for tolerance. Twenty-four patients (64.8%) achieved objective responses. The median duration of response was 17.5 months (range 2.5-57 months), median time to progression was 13.2 months (range 0.4-57 months) and median survival was 20.6 months (range 0.4-55 months). This regimen was well-tolerated; no WHO grade 4 neutropenia was observed, grade 3 nausea and vomiting occured in 50% of patients and grade 2 peripheral neuropathy in 5% of patients. Conclusion: Vinorelbine-cisplatin is an active and well-tolerated regimen in advanced cervical carcinoma.

PURPOSEThe purpose of this multi-institutional phase II trial was to evaluate the efficacy and toxicity of doxorubicin and docetaxel plus granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer. The primary objective was to determine whether the combination produced a response rate of at least 50%.PATIENTS AND METHODSFifty-four patients with metastatic breast cancer received doxorubicin (60 mg/m(2) by intravenous [IV] injection) followed 1 hour later by docetaxel (60 mg/m(2) by IV infusion over 1 hour) every 3 weeks for up to eight cycles. All patients also received G-CSF.RESULTSObjective response occurred in 29 (57%) of 51 eligible patients (95% confidence interval [CI], 42% to 70%), including three patients who had a complete response (6%; 95% CI, 1% to 16%). The median response duration was 7 months (95% CI, 6.0 to 15.0 months), median time to treatment failure was 7. 6 months (95% CI, 6.2 to 9.9 months), and the median survival was 27. 5 months (95% CI, 21.5 months to upper limit not reached). The median cumulative doxorubicin dose was 395 mg/m(2) (range, 60 to 480 mg/m(2)). Fifteen patients (28%) were documented to have a decrease in the left ventricular ejection fraction below normal, and three patients (6%; 95% CI, 1% to 15%) developed congestive heart failure.CONCLUSIONUsing criteria that we had defined a priori, the doxorubicin-docetaxel regimen as used in this study was sufficiently active and tolerable to justify a phase III comparison with doxorubicin-cyclophosphamide in early-stage breast cancer.

Seventeen patients with enhanced measurable squamous cell carcinoma of the esophagus were treated with topotecan 1.5 mg/m2 daily for 5 days repeated every 21 days. Toxicity was severe, with 1 death from myelotoxicity and 10 patients with life-threatening myelotoxicity. Severe gastrointestinal toxicity consisting of vomiting was also seen in three patients. No response was seen in any of the patients in the study. Topotecan given in this manner has no activity in squamous cell carcinoma of the esophagus.

PURPOSE:The identification of a subset of patients with axillary lymph node-positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node-positive breast cancer and compare these parameters with other established prognostic factors. PATIENTS AND METHODS:This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node-positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients. RESULTS:Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P </=.01). Within the first 5 years of follow-up, mitotic index (P =.004), grade (P =.004), ploidy (P =. 006), and SPF (P =.05) were associated with time to recurrence; there was also a significant association with survival. The effect of mitotic index was largely a result of the difference between 0 to 2 mitoses/10 high-power fields (HPF; 5-year recurrence of 31%) and more than 2 mitoses/10 HPF (5-year recurrence of 52%). The 0 to 2 mitoses/10 HPF group was independently associated with improved prognosis at 5 years (P =.002) in regression models that included other standard prognostic factors. CONCLUSION:A subset of axillary lymph node-positive patients with improved prognosis may be identified using a lower (< 3 mitoses/10 HPF) mitotic count than is usually performed.

PURPOSE:To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure (LRF) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation.PATIENTS AND METHODS:The study population consisted of 2,016 patients entered onto four randomized trials conducted by the Eastern Cooperative Oncology Group. The median follow-up time for patients without recurrence was 12.1 years (range, 0.07 to 19.1 years).RESULTS:A total of 1,099 patients (55%) experienced disease recurrence. The first sites of failure were as follows: isolated LRF, 254 (13%); LRF with simultaneous distant failure (DF), 166 (8%); and distant only, 679 (34%). The risk of LRF with or without simultaneous DF at 10 years was 12.9% in patients with one to three positive nodes and 28.7% for patients with four or more positive nodes. Multivariate analysis showed that increasing tumor size, increasing numbers of involved nodes, negative estrogen receptor protein status, and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF.CONCLUSION:LRF after mastectomy is a substantial clinical problem, despite the use of chemotherapy with or without tamoxifen. Prospective randomized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens.

PURPOSE Several groups have reported that the combination of doxorubicin plus paclitaxel given as a 3-hour intravenous (IV) infusion for up to eight cycles produces a high response rate (> 80%) and complete response rate (> 20%) in metastatic breast cancer, but is also complicated by a 20% incidence of congestive heart failure (CHF). The purpose of this phase II trial was to evaluate the antineoplastic activity of the regimen in a multi-institutional setting and to reduce the incidence of cardiotoxicity by limiting treatment to a maximum of six cycles. PATIENTS AND METHODS Fifty-two patients with advanced breast cancer received doxorubicin (60 mg/m(2) by IV injection) followed 15 minutes later by paclitaxel (200 mg/m(2) by IV infusion over 3 hours) every 3 weeks for four to six cycles. RESULTS Objective responses occurred in 25 of 48 assessable patients (52%; 95% confidence interval [CI], 38% to 66%), including four complete responses (8%; 95% CI, 0% to 16%). The median cumulative doxorubicin dose given was 240 mg/m(2) (range, 132 to 360 mg/m(2)). Eleven patients (21%) were documented as having a decrease in the LVEF below normal, including three patients (6%; 95% CI, 0% to 12%) who developed CHF. CONCLUSION The doxorubicin/paclitaxel regimen that we used is unlikely to produce an objective response rate of more than 70% and a complete response rate of more than 20% in patients with metastatic breast cancer, and proved to be excessively cardiotoxic for use in the adjuvant setting.

The riminophenazine compound clofazimine has been shown to be a potent inhibitor of hepatocellular carcinoma (HCC) in vitro. Therapeutic benefit was claimed for patients with HCC treated with clofazimine in a recent clinical trial. The current trial was initiated to evaluate response and survival of patients with HCC receiving clofazimine plus doxorubicin. Twenty-eight patients were entered into the study, of whom 27 were evaluable for response and survival. No patients had a complete or partial response, and 9 had stable disease. The median survival time was 7 weeks. Toxicity was mild with yellow pigmentation of the skin resulting from the clofazimine, and leukopenia, nausea, vomiting and mucositis as expected from doxorubicin. Further studies using other riminophenazine compounds are warranted.

Locoregional recurrence is a harbinger of disseminated disease, and historically the estimated 5-year survival when treated with local therapy only varies between 21% and 37%. The role of systemic treatment after local treatment is unclear at present. The authors investigated the results of systemic chemotherapy for these patients after complete local surgical resection. Data on 80 patients were evaluable for toxicity, time to treatment failure (TTF), and survival. Sixty-four patients received doxorubicin-based treatments, four received methotrexate-based combinations, and 12 received tamoxifen only. Among the 68 patients treated with cytostatics, there were two possible treatment-related deaths. Two patients developed grade 3 neutropenia, four developed grade 3 vomiting, and 42 had grade 2 toxicity. The 2- and 5-year disease free survival at a mean follow-up period of 5.5 years were 56% and 38%, respectively. The projected median TTF was 32 months (95% confidence interval, 23-82). Two- and 5-year overall survival were 86% and 62%, respectively, with a projected median survival of 93 months (7.75 years; 95% confidence interval, 64-177). These results show systemic therapy improved TTF and survival for patients with stage IV, no-evidence-of-disease breast cancer. Randomized studies are needed to confirm these findings and define optimal therapy.

PURPOSETo investigate the response rate, time to treatment failure (TTF), overall survival, and toxicity in patients with metastatic melanoma treated with dacarbazine alone, dacarbazine plus interferon (IFN), dacarbazine plus tamoxifen (TMX), or dacarbazine plus IFN plus TMX.MATERIALS AND METHODSTwo hundred seventy-one patients (258 were eligible) were randomized in a 2 x 2 factorial design to receive one of the above treatments. The trial was designed to detect a 50% improvement in survival with 83% power.RESULTSNine complete (CRs) and 18 partial responses (PRs) were observed in the patients who received treatments that contained IFN compared with four CRs and 18 PRs in the patients who received treatments that did not contain IFN. Five CRs and 20 PRs occurred in patients treated with TMX compared with eight CRs and 16 PRs in those treated without TMX. Response differences were nonsignificant. The overall median TTF was 2.6 months, and the overall median survival was 8.9 months. There was no significant difference in TTF or survival among any of the different treatments. Poor performance status (PS), hepatic metastases, and weight loss were significant adverse prognostic factors. Twenty-three patients had a TTF greater than 20 months, and these durable responses were evenly distributed among the treatment arms. Significantly more severe and life-threatening toxic events occurred with treatments that contained IFN.CONCLUSIONNeither IFN, TMX, nor the combination significantly improved the response rate, TTF, or survival when added to dacarbazine, but IFN significantly increased toxicity.

Prognostic factors in 236 patients with metastatic malignant melanoma were analyzed. The patients were all entered on clinical research studies at a single institution. Univariate and multivariate analyses were performed on data which was prospectively collected. Seven independent variables were analyzed for effect on response, time to treatment failure (TTF) and survival. Univariate analysis identified four factors which significantly effected response, TTF and survival: PS, dominant site of disease, number of sites of disease and treatment. In multivariate analyses dominant site of disease and treatment remained significant factors influencing response rates, but performance status (PS) and number of sites of metastases lost statistical significance. Treatment and number of sites were significant for TTF and treatment, PS and disease-free interval were significant for survival. The identification of prognostic factors may lead to identification of subgroups of patients who may benefit from existing treatment programs, and may allow for new treatment programs to be designed with greater insight, logic and rationale.

Carcinoma of unknown primary (CUP) site accounts for approximately 6.5% of all cancers. Optimal therapy for patients with CUP has not yet been delineated. The current study was undertaken to evaluate response, time to treatment failure and survival in patients with CUP treated with a combination regimen comprising mitomycin C, epirubicin and cisplatin (MEP) versus mitomycin C alone (MITOC). Eighty-four patients with CUP were randomised to receive either the combination (MEP) or MITOC. Both treatment arms were well matched for age, gender, performance status, dominant site and number of disease sites. Eighty of the above patients were evaluable. Twenty patients (50%) treated with MEP responded to treatment compared with 7 (17%) who received MITOC. Grade III-IV hemopoietic toxicity was documented in 2 patients treated with MEP and no patients treated with MITOC. A single patient treated with MEP developed grade I peripheral neuropathy. Median time to treatment failure was 4.5 months for patients receiving MEP as opposed to 2 months for those receiving MITOC (p = 0.05). Median survival was 9.4 months in patients treated with MEP compared to 5.4 months in those receiving MITOC (p = 0.05). This study indicates that the addition of cisplatin and epirubicin to MITOC results in a significant improvement in the response rate, time to treatment failure and survival in patients with adenocarcinoma of unknown primary site.