Identifying oncogenic drivers associated with increased risk of late distant recurrence in postmenopausal, estrogen receptor-positive, HER2-negative early breast cancer: results from the BIG 1-98 study.

BACKGROUND: In postmenopausal, estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer, the risk for distant recurrence can extend beyond 5 years of adjuvant endocrine therapy. This study aims to identify genomic driver alterations associated with late distant recurrence. PATIENTS AND METHODS: Next generation sequencing was used to characterize driver alterations in primary tumors from a subset of 764 postmenopausal estrogen receptor-positive/HER2-negative patients from the BIG 1-98 randomized trial. Late distant recurrence events were defined as ≥5 years from time of randomization). The association of driver alterations with distant recurrence-free interval in early and late time periods was assessed using Cox regression models. Multivariable analyses were carried out to adjust for clinicopathological factors. Weighted analysis methods were used in order to correct for over-sampling of distant recurrences. RESULTS: A total of 538 of 764 (70%) samples were successfully sequenced including 88 (63%) early and 52 (37%) late distant recurrence events after a median follow up of 8.1 years. In univariable analysis for late distant recurrence, PIK3CA mutations (58.8%) were significantly associated with reduced risk [hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.20-0.82, P = 0.012], whereas amplifications on chromosome 8p11 (10.9%) (HR 4.79, 95% CI 2.30-9.97, P < 0.001) and BRCA2 mutations (2.3%) (HR 5.39, 95% CI 1.51-19.29, P = 0.010) were significantly associated with an increased risk. In multivariable analysis, only amplifications on 8p11 (P = 0.002) and BRCA2 mutations (P = 0.013) remained significant predictors. CONCLUSIONS: In estrogen receptor-positive/HER2-negative postmenopausal early breast cancer, PIK3CA mutations were associated with reduced risk of late distant recurrence, whereas amplifications on 8p11 and BRCA2 mutations were associated with increased risk of late distant recurrence. The characterization of oncogenic driver alterations may aid in refining treatment choices in the late disease setting, and help identify potential drug targets for testing in future trials.

Off-label use of anticancer drugs in eastern Switzerland: a population-based prospective cohort study.

PURPOSE: Prevalence data on the off-label use (OLU) of anticancer drugs are limited despite OLU being controversial for medical, pharmaco-economic, and ethical reasons. We therefore quantified and characterized the OLU of anticancer drugs and compared OLU based on the national drug label with international treatment recommendations. METHODS: We prospectively collected data on patients receiving systemic anticancer therapy between October and December 2012 at hospitals affiliated with the Eastern Switzerland Oncology Network. Individual data on patient characteristics, tumor disease, and systemic treatment were collected, and each individual treatment was compared with the national drug label and international treatment guidelines. RESULTS: A total of 985 consecutive patients receiving 1,737 anticancer drug treatments were included in the study. Overall, 32.4 % of all patients received at least one off-label drug, corresponding to 27.2 % of all anticancer drugs administered. Major reasons for OLU were the lack of approval for the specific disease entity (15.7 %) and modified application of the anticancer drug (10 %). OLU that was unsupported by the current European Society for Medical Oncology (ESMO) treatment recommendations was rare (6.6 %) but higher for bevacizumab (29.6 %) due to its use in treating advanced ovarian cancer beyond the second-line setting and advanced breast cancer beyond the first-line setting and for lenalidomide (22.6 %) due to its use in treating Non-Hodgkin lymphoma. CONCLUSIONS: Based on data collected on our patient cohort, OLU of anticancer drugs in a European clinical setting applies to one-third of all cancer patients. ESMO-unsupported use of chemotherapies or molecularly-targeted drugs is rare, opposing concerns that the off-label use of newer anticancer drugs is a substantial clinical problem.

Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with estrogen receptor-positive, HER-2-positive advanced breast cancer: a proof-of-concept trial (SAKK 23/03).

A sequential treatment design was chosen in this trial to ensure complete resistance to single-agent non-steroidal aromatase inhibitor (AI) and trastuzumab both given as monotherapy before receiving the combination of a non-steroidal AI and trastuzumab. Key eligibility criteria included postmenopausal patients with advanced, measurable, human epidermal growth factor receptor-2 (HER-2)-positive disease (assessed by FISH, ratio (≥2)), hormone receptor (HR)-positive disease, and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in the adjuvant or in the advanced setting. Patients received standard dose trastuzumab monotherapy in step 1 and upon disease progression continued trastuzumab in combination with letrozole in step 2. The primary endpoint was clinical benefit rate (CBR) in step 2. Totally, 13 patients were enrolled. In step 1, six patients (46%) achieved CBR. Median time to progression (TTP) was 161 days (95% confidence interval (CI): 82-281). In step 2, CBR was observed in eight out of the 11 evaluable patients (73%), including one patient with partial response. Median TTP for all the 11 patients was 188 days (95% CI: 77-not reached). Results of this proof-of-concept trial suggest that complete resistance to both AI and trastuzumab can be overcome in a proportion of patients by combined treatment of AI and trastuzumab, as all patients served as their own control. Our results appear promising for a new treatment strategy that offers a chemotherapy-free option for at least a subset of patients with HR-positive, HER-2-positive breast cancer over a clinically relevant time period.

Low-Dose Fulvestrant Maintained Long-Term Complete Remission after Poor Response to Previous Endocrine Therapies in a Patient with Advanced Breast Cancer.

We report a case of long-term (9 years) response to 4th-line endocrine treatment with fulvestrant given for advanced breast cancer after no or poor response to prior endocrine therapies. Complete remission was achieved with full dose and maintained even after dose reduction due to unanticipated intensity of mucosal toxicity. Complete remission was temporarily lost after fulvestrant was tentatively withdrawn (63 months after treatment start), but was re-achieved after renewal of half-dose treatment and last reconfirmed 90 months after treatment start. The pharmacokinetic profile provides evidence to hypothesize a unique sensitivity to fulvestrant in this patient which might explain both: toxicity and extraordinary efficacy.

Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study.

Twenty-one adult patients were randomised to receive ghrelin on days 1 and 8 and placebo on days 4 and 11 or vice versa, given intravenously over a 60-min period before lunch: 10 received 2 microg kg(-1) (lower-dose) ghrelin; 11 received 8 microg kg(-1) (upper-dose) ghrelin. Active and total ghrelin, growth hormone (GH), and insulin-like growth factor 1 levels were monitored at baseline (4-5 days before day 1), during treatment days, and at end of study (day 17/18). Drug-related adverse events (assessed by NCI-CTC-toxicity criteria and cardiac examination) did not differ between ghrelin and placebo. No grade 3/4 toxicity or stimulation of tumour growth was observed. The peak increase of GH, a biological marker of ghrelin action, was 25 ng ml(-1) with lower-dose and 42 ng ml(-1) with upper-dose ghrelin. Morning fasting total ghrelin levels were higher (P<0.05) for upper-dose patients at end of study (3580 pg ml(-1)) than at baseline (990 pg ml(-1)). Insulin-like growth factor 1 levels did not change. At day 8, 81% of patients preferred ghrelin to placebo as against 63% at the end of study. Nutritional intake and eating-related symptoms, measured to explore preliminary efficacy, did not differ between ghrelin and placebo. Ghrelin is well tolerated and safe in patients with advanced cancer. For safety, tolerance, and patients' preference for treatment, no difference was observed between the lower- and upper-dose group.

Therapeutic impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography in the pre- and postoperative staging of patients with clinically intermediate or high-risk breast cancer.

BACKGROUND: Positron emission tomography with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG-PET) is an accurate imaging modality for the staging of breast cancer. The aim of this study was to determine the potential therapeutic impact of pre- and postoperative FDG-PET in patients with clinically intermediate or high-risk breast cancer. PATIENTS AND METHODS: One hundred and fourteen patients with newly diagnosed breast cancer were examined before (73) or after (41) surgery. Patient data were translated into three scoring sheets corresponding to information available before positron emission tomography (PET), after PET and after further diagnostic tests. Three medical oncologists independently reviewed the retrospectively acquired patient data and prospectively made decisions on the theoretically planed treatment for each time point, according to the recommendations of St Gallen Consensus Guidelines 2005. RESULTS: FDG-PET changed the planed treatment in 32% of 114 patients. In 20% of cases, therapeutic intention (curative versus palliative) was modified. Radiation treatment planning was changed in 27%, surgical planning in 9%, chemotherapy in 11% and intended therapy with bisphosphonates in 13% of all patients. CONCLUSION: Based on current treatment guidelines, FDG-PET, as a staging procedure in patients with newly diagnosed clinically intermediate or high-risk breast cancer examined pre- and postoperatively, may have a substantial therapeutic impact on treatment planning.

A randomized double-blind trial to compare the clinical efficacy of granisetron with metoclopramide, both combined with dexamethasone in the prophylaxis of chemotherapy-induced delayed emesis.

BACKGROUND: The prophylactic use of 5-HT(3) receptor antagonists (setrons), after the first 24 h (acute phase) of exposure to emetic chemotherapy, to decrease the incidence of 'delayed phase' emesis increases costs. We designed a study to evaluate the efficacy of a setron (granisetron) in the delayed phase, compared with metoclopramide, each combined with a corticosteroid. PATIENTS AND METHODS: Patients on their first course of single-day emetic chemotherapy (cisplatin, carboplatin, doxorubicin, cyclophosphamide and others) received granisetron 2 mg p.o. and dexamethasone 8 mg p.o. on day 1, followed for 5 days by dexamethasone 4 mg p.o. od combined with either metoclopramide 20 mg p.o. tds or granisetron 1 mg bd in a double-blinded double-dummy protocol. Patients evaluated the results using a diary card. Randomization was stratified by institution, sex, emetic chemotherapy naïve versus previous, alcohol consumption and platinum versus non-platinum regimen. RESULTS: 131 evaluable patients received granisetron in the delayed phase, and 127 received metoclopramide. Control of acute emesis in both arms was similar (86% granisetron; 85% metoclopramide). The 35 patients experiencing acute emesis had poor control in the delayed phase, with only four granisetron and three metoclopramide patients having no or mild nausea and no vomiting. CONCLUSIONS: In daily practice, a combination of oral dexamethasone and oral granisetron achieves an extremely high control of acute emesis (86% protection). Our data suggest that routine prescription of setrons for delayed phase control is not advisable as it increases costs without any benefit for the majority of patients. Delayed emesis in the rare patients with acute phase emesis remains an unsolved problem.

Economic analysis of terminal care for patients with malignant osteolytic bone disease and pain treated with pamidronate.

The goals of this study were the assessment (1) of all costs of terminal care of patients with osteolytic bone disease and pain and (2) of the economic consequences of the pamidronate treatment as observed in a prospective clinical trial on the effectiveness of pamidronate. A total of 70 patients were recruited, who were all suffering from advanced tumour diseases (60% breast cancer, 21% multiple myeloma, and 19% other tumours). In a single-institution study the patients were randomly assigned to receive, in a double-blinded setting, pamidronate 60 mg i.v. or 90 mg i.v. every 3 weeks for a maximum of six cycles. Perception of pain intensity was recorded by self-assessment, using a linear analogue scale. Follow-up lasted 6 months after treatment. All elements of direct costs of in-patient and out-patient care were recorded in cooperation with the hospital administration and the health insurance companies [Krankenkassen]. Average monthly direct costs amounted to ECU 1,290 (+/-410) and 1,050 (+/- 430) during the treatment phase and follow-up, respectively. Average in-patient costs were about three times the out-patient costs. Significantly higher costs (by a factor of 2) were observed for terminal care in hospital (last 3 months before death) than for continued care (of patients surviving the study period). The treatment with pamidronate reduced pain significantly but did not add noticeably to the costs. The study showed that it is practicable and quite efficient to combine a pharmaco-economic evaluation with a clinical trial, although it may be difficult (depending on the setting and availability of information) to assess true costs, i.e. total resource usage.

Pamidronate treatment in patients with malignant osteolytic bone disease and pain: a prospective randomized double-blind trial.

The aim of this double-blind, randomized study was to compare the effects of two pamidronate dosages, given as repeated infusions in patients with advanced malignant osteolytic bone disease and bone pain. Seventy patients were randomly assigned to receive pamidronate 60 mg or 90 mg i.v. every 3 weeks for a maximum of six cycles. Pain parameters, analgesic consumption and performance status were assessed at baseline and throughout the study. Furthermore, total-body bone mineral density was measured using dual-energy X-ray absorptiometry at baseline, after three and after six infusions. Sixty percent (95% CI 41-77%) of the patients in the 60 mg group and 63% (95% CI 44-79%) of the patients in the 90-mg group had a sustained reduction of pain intensity and were classified as pain responders. Median duration of pain response was 15 versus 12 weeks in the 60-mg and 90-mg groups, respectively (P = 0.32). After two infusions, significant changes in pain intensity, pain frequency, general well-being and WHO pain score were observed (P<0.01). A trend toward improved performance status and reduced consumption of analgesics was also observed. Patients in the 90-mg group had more pronounced bone remineralization as measured by total-body bone mineral density. No significant difference was detectable between the two pamidronate treatments in any of the parameters evaluated. In conclusion, bone pain can be effectively reduced by repeated pamidronate infusions in patients with advanced osteolytic bone disease. Pamidronate 90 mg every 3 weeks results in higher bone remineralization, but this difference did not translate into a further increase of palliative effects.

Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer.

Agents capable of reversing P-glycoprotein-associated multidrug resistance have usually failed to enhance chemotherapy activity in patients with solid tumours. Based on its toxicity profile and experimental potency, dexverapamil, the R-enantiomer of verapamil, is considered to be promising for clinical use as a chemosensitizer. The purpose of this early phase II trial was to evaluate the effects of dexverapamil on epirubicin toxicity, activity and pharmacokinetics in patients with metastatic breast cancer. A two-stage design was applied. Patients first received epirubicin alone at 120 mg m(-2) i.v. over 15 min, repeated every 21 days. Patients with refractory disease continued to receive epirubicin at the same dose and schedule but supplemented with oral dexverapamil 300 mg every 6 h x 13 doses. The Gehan design was applied to the dexverapamil/epirubicin cohort of patients. Thirty-nine patients were entered on study, 25 proceeded to receive epirubicin plus dexverapamil. Dexverapamil did not increase epirubicin toxicity. The dose intensity of epirubicin was similar when used alone or with dexverapamil. In nine intrapatient comparisons, the area under the plasma concentration-time curve (AUC) of epirubicin was significantly reduced by dexverapamil (mean 2968 vs 1901 microg ml[-1] h[-1], P= 0.02). The mean trough plasma levels of dexverapamil and its major metabolite nor-dexverapamil were 1.2 and 1.5 microM respectively. The addition of dexverapamil to epirubicin induced partial responses in 4 of 23 patients evaluable for tumour response (17%, CI 5-39%, s.e.P 0.079). The remissions lasted 3, 8, 11 and 11+ months. These data suggest that the concept of enhancing chemotherapy activity by adding chemosensitizers may function not only in haematological malignancies but also in selected solid tumours. An increase in the AUC and toxicity of cytotoxic agents does not seem to be a prerequisite for chemosensitizers to enhance anti-tumour activity.

Diagnostic and prognostic value of biochemical markers in malignant bone disease: a prospective study on the effect of bisphosphonate on pain intensity and progression of malignant bone disease.

Seventy cancer patients with malignant osteolytic bone disease received pamidronate every three weeks for a maximum of six cycles. Bone resorption parameters, urinary calcium excretion, and pain parameters were assessed at baseline and throughout the study. At baseline, 80-95% of patients showed elevated urinary pyridinoline, deoxypyridinoline, Osteomark NTx and serum ICTP levels, whereas only 35% of patients had elevated urinary CrossLaps excretion rates. During bisphosphonate therapy, significant decreases in Osteomark NTx, CrossLaps and calcium excretion were observed, which were not related to the clinical outcome. The baseline levels of bone resorption markers were used to predict the probability of non-progressive bone disease or reduction in pain intensity during bisphosphonate therapy. Significant predictors of non-progressive bone disease were urinary pyridinoline and serum ICTP levels; significant predictors of reduction in pain intensity were urinary free deoxypyridinoline and serum ICTP levels. Our data indicate that serum ICTP levels predict significantly the response to bisphosphonate therapy in patients with advanced malignant osteolytic bone disease. CrossLaps did not predict the clinical outcome, but decreased significantly during bisphosphonate therapy. Our data demonstrate that the different bone resorption markers are reflecting different aspects of bone metabolism, and therefore differ in their diagnostic and prognostic properties.

Docetaxel vs mitomycin plus vinblastine in anthracycline-resistant metastatic breast cancer.

This nonblinded, multicenter, randomized phase III study compares the median time to progression (primary endpoint), response rate, and quality of life, safety, and survival of docetaxel (Taxotere) vs mitomycin (Mutamycin) plus vinblastine (Velban) in patients with metastatic breast cancer in whom previous anthracycline-containing chemotherapy has failed. Patients were randomized to receive an intravenous infusion of either 100 mg/m2 of docetaxel for 1 hour every 3 weeks, or 12 mg/m2 of mitomycin every 6 weeks plus 6 mg/m2 of vinblastine every 3 weeks. This preliminary analysis presents data on 200 patients among 392 patients recruited. Median time to progression was longer in the group treated with docetaxel compared with the mitomycin/vinblastine group (17 vs 9 weeks). The overall response rates were higher with docetaxel (28% vs 13%, respectively), and fewer patients in the docetaxel group had progressive disease as their best overall response (29% vs 48%). As expected, thrombocytopenia was more common in the mitomycin/vinblastine group, and neutropenia occurred more frequently in the docetaxel group. Severe fluid retention in the docetaxel group (8.7%) resulted in treatment discontinuation in 5 patients (5%). Severe thrombocytopenia (12%) and constipation (6%) led to treatment discontinuation in 7 and 3 patients, respectively, in the mitomycin/vinblastine group. Based on this preliminary analysis, docetaxel appears to be equally as safe as and more active than mitomycin/ vinblastine in patients with metastatic breast cancer in whom previous anthracycline-containing chemotherapy has failed. These results are subject to cautious interpretation because this analysis was conducted on the first 200 patients who finished the study treatments, and these preliminary results may underestimate response and overstate treatment discontinuation rates. Thus, the final analysis on the entire patient population is necessary to confirm these preliminary findings.

A phase II trial of 5-fluorouracil and 1-leucovorin in patients with metastatic colorectal cancer.

We undertook a multicenter phase II trial of 5-fluorouracil (5FU) + 1-leucovorin (1-LV) in previously untreated patients with metastatic colorectal cancer to determine the response rate, response duration, time to progression, survival, and toxicity. Patients were treated with i.v. 5FU 370 mg/m2/day and 1-LV 100 mg/m2/day x 5 every 28 days. Toxicity and response were determined by WHO criteria. One hundred and twenty-six patients were entered, and 119 patients were eligible and evaluable. Eighty-eight patients had colon cancer and 37 had rectal cancer. The male:female ratio was 58:68. The mean age was 62.2 years. ECOG performance status distribution was 0 (39.7%), 1 (46%), and 2 (11.9%). The median number of courses of therapy administered was 4.5. Severe- or life-threatening stomatitis or diarrhea, nausea, and granulocytopenia occurred in 17.6, 23.2, 17.6, and 15.9% of patients, respectively. The response rate was 22/119 [18.5%; 95% confidence interval (CI) of 12.0-26.6]. Median response duration was 188 days (95% CI of 111-248 days). Median survival was 379 days (95% confidence interval of 289-452 days). These results indicate that when 1-LV is combined with 5FU, toxicity is similar in pattern and severity to that of the d,1 racemic mixture. The overall efficacy of 1-LV + 5FU is comparable to a recent metaanalysis.