Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer

Surrogate markers may help predict the effects of first-line treatment on survival. This metaregression analysis examines the relationship between several surrogate markers and survival in women with advanced breast cancer after receiving first-line combination anthracycline chemotherapy 5-fluorouracil, adriamycin and cyclophosphamide (FAC) or 5-fluorouracil, epirubicin and cyclophosphamide (FEC) . From a systematic literature review, we identified 42 randomised trials. The surrogate markers were complete or partial tumour response, progressive disease and time to progression. The treatment effect on survival was quantified by the hazard ratio. The treatment effect on each surrogate marker was quantified by the odds ratio (or ratio of median time to progression). The relationship between survival and each surrogate marker was assessed by a weighted linear regression of the hazard ratio against the odds ratio. There was a significant linear association between survival and complete or partial tumour response (P<0.001, R2=34%), complete tumour response (P=0.02, R2=12%), progressive disease (P<0.001, R2=38%) and time to progression (P<0.0001, R2=56%); R2 is the proportion of the variability in the treatment effect on survival that is explained by the treatment effect on the surrogate marker. Time to progression may be a useful surrogate marker for predicting survival in women receiving first-line anthracycline chemotherapy and could be used to estimate the survival benefit in future trials of first-line chemotherapy compared to FAC or FEC. The other markers, tumour response and progressive disease, were less good

Combination chemotherapy with or without s.c. IL-2 and IFN-α: results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy Group (ACIMM)

The purpose of this randomized trial was to evaluate the efficacy of combination chemoimmunotherapy compared with chemotherapy alone. A total of 124 patients were randomized to receive intravenous cisplatin (35 mg m−2, days 1–3), carmustine (150 mg m−2, day 1, cycles 1 and 3 only), dacarbacine (220 mg m−2, days 1–3) and oral tamoxifen (20 mg m−2, daily) in combination with (n=64) or without (n=60) sequential subcutaneous IL-2 and IFN-α. In those patients who received sequential immunotherapy, each cycle of chemotherapy was followed by outpatient s.c. IL-2 (10×106 IU m−2, days 3–5, week 4; 5×106 IU m−2, days 1, 3, 5, week 5) and s.c. IFN-α (5×106 IU m−2, day 1, week 4; days 1, 3, 5, week 5). The overall response rate of patients treated with the combination of chemotherapy and IL-2/IFN-α was 34.3% with seven complete responses (10.9%) and 15 partial responses (23.4%). In patients treated with chemotherapy, only, the overall response rate was 29.9% with eight complete responses (13.3%) and 10 partial responses (16.6%). There was no significant difference in median progression free survival (0 months vs 4 months) and in median overall survival (12 months vs 13 months) for combined chemoimmunotherapy and for chemotherapy, respectively

Low back pain as the presenting sign in a patient with primary extradural melanoma of the thoracic spine - A metastatic disease 17 Years after complete surgical resection

Primary spinal melanomas are extremely rare lesions. In 1906, Hirschberg reported the first primary spinal melanoma, and since then only 40 new cases have been reported. A 47-year-old man was admitted suffering from low back pain, fatigue and loss of body weight persisting for three months. He had a 17-year-old history of an operated primary spinal melanoma from T7-T9, which had remained stable for these 17 years. Routine laboratory findings and clinical symptoms aroused suspicion of a metastatic disease. Multislice computed tomography and magnetic resonance imaging revealed stage-IV melanoma with thoracic, abdominal and skeletal metastases without the recurrence of the primary process. Transiliac crest core bone biopsy confirmed the diagnosis of metastatic melanoma. It is important to know that in all cases of back ore skeletal pain and unexplained weight loss, malignancy must always be considered in the differential diagnosis, especially in the subjects with a positive medical history. Patients who have back, skeletal, or joint pain that is unresponsive to a few weeks of conservative treatment or have known risk factors with or without serious etiology, are candidates for imaging studies. The present case demonstrates that complete surgical resection alone may result in a favourable outcome, but regular medical follow-up for an extended period, with the purpose of an early detection of a metastatic disease, is highly recommended

Melanoma: A model for testing new agents in combination therapies

Treatment for both early and advanced melanoma has changed little since the introduction of interferon and IL-2 in the early 1990s. Recent data from trials testing targeted agents or immune modulators suggest the promise of new strategies to treat patients with advanced melanoma. These include a new generation of B-RAF inhibitors with greater selectivity for the mutant protein, c-Kit inhibitors, anti-angiogenesis agents, the immune modulators anti-CTLA4, anti-PD-1, and anti-CD40, and adoptive cellular therapies. The high success rate of mutant B-RAF and c-Kit inhibitors relies on the selection of patients with corresponding mutations. However, although response rates with small molecule inhibitors are high, most are not durable. Moreover, for a large subset of patients, reliable predictive biomarkers especially for immunologic modulators have not yet been identified. Progress may also depend on identifying additional molecular targets, which in turn depends upon a better understanding of the mechanisms leading to response or resistance. More challenging but equally important will be understanding how to optimize the treatment of individual patients using these active agents sequentially or in combination with each other, with other experimental treatment, or with traditional anticancer modalities such as chemotherapy, radiation, or surgery. Compared to the standard approach of developing new single agents for licensing in advanced disease, the identification and validation of patient specific and multi-modality treatments will require increased involvement by several stakeholders in designing trials aimed at identifying, even in early stages of drug development, the most effective way to use molecularly guided approaches to treat tumors as they evolve over time

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment

Abstract OT3-06-06: 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 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 &amp;gt;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.</jats:p

Abstract P1-11-24: Concurrent and Sequential Bevacizumab and Preoperative Chemotherapy in the Treatment of Locally Advanced Breast Cancer: UAB 0493

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 &amp;gt; 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 &amp;gt;150/90 in 7 patients. 12 doses of bevacizumab were held due to a blood pressure &amp;gt; 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 &amp; from Genentech Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-24.</jats:p

P3-14-31: Preoperative Chemotherapy and Bevacizumab for Locally Advanced HER-2 Negative Breast Cancer Followed by Prolonged Postoperative Bevacizumab for Those with Less Than Complete Pathologic Response.

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 &amp;gt;55% before and after completing CT; no cardiac failure was seen. Grade III toxicities included hypertension &amp;gt;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.</jats:p