Trastuzumab and first-line taxane chemotherapy in metastatic breast cancer patients with a HER2-negative tumor and HER2-positive circulating tumor cells: a phase II trial.

PURPOSE: HER2 overexpressing circulating tumor cells (CTCs) are observed in up to 25% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically improved clinical outcomes of patients with HER2-positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy. METHODS: In this single-arm, phase II trial, patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy. Patients with detectable CTCs but without HER2 overexpression that received taxane chemotherapy only, were used as control group. The primary outcome measure was progression-free rate at 6 months (PFR6), with a target of 80%. In November 2022, the study was terminated early due to slow patient accrual. RESULTS: 63 patients were screened, of which eight patients had HER2-positive CTCs and were treated with trastuzumab. The median number of CTCs was 15 per 7.5 ml of blood (range 1-131) in patients with HER2-positive CTCs, compared to median 5 (range 1-1047) in the control group. PFR6 was 50% in the trastuzumab group and 54% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p = 0.51). CONCLUSION: No clinical benefit of trastuzumab was observed, although this study was performed in a limited number of patients. Additionally, we observed a strong correlation between the number of evaluable CTCs and the presence of HER2-positive CTCs. We argue that randomized studies investigating agents that are proven to be solely effective in the HER2-positive patient group in patients with HER2-positive CTCs and HER2-negative tissue are currently infeasible. Several factors contribute to this impracticality, including the need for more stringent thresholds, and the rapidly evolving landscape of cancer treatments.

Tumor-agnostic ctDNA levels by mFAST-SeqS in first-line HR-positive, HER2 negative metastatic breast cancer patients as a biomarker for survival.

This prospective cohort study reports aneuploidy score by mFast-SeqS as a strong prognostic marker in MBC patients. mFAST-SeqS is an affordable and easily implementable method for the assessment of total ctDNA levels and, as such, provides an alternative prognostic tool. One mixed cohort (cohort A, n = 45) starting any type of treatment in any line of therapy and one larger cohort (cohort B, n = 129) consisting of patients starting aromatase inhibitors (AI) as first-line therapy were used. mFAST-SeqS was performed using plasma of blood in which CTCs (CellSearch) were enumerated. The resulting aneuploidy score was correlated with categorized CTC count and associated with outcome. The aneuploidy score was significantly correlated with CTC count, but discordance was observed in 31.6% when applying cut-offs of 5. In both cohorts, aneuploidy score was a significant prognostic marker for both PFS and OS. In the Cox regression models, the HR for aneuploidy score for PFS was 2.52 (95% CI: 1.56-4.07), and the HR for OS was 2.37 (95% CI: 1.36-4.14). Results presented here warrant further investigations into the clinical utility of this marker in MBC patients.

Patients' perceptions of 70-gene signature testing: commonly changing the initial inclination to undergo or forego chemotherapy and reducing decisional conflict.

PURPOSE: Little is known about the impact of 70-gene signature (70-GS) use on patients' chemotherapy decision-making. The primary aim of this study was to evaluate the impact of 70-GS use on patients' decisions to undergo chemotherapy. The perceived decision conflict during decision-making was a secondary objective of the study. METHODS: Patients operated for estrogen receptor positive early breast cancer were asked to fill out a questionnaire probing their inclination to undergo chemotherapy before deployment of the 70-GS test. After disclosure of the 70-GS result patients were asked about their decision regarding chemotherapy. Patients' decisional conflict was measured using the 16-item decisional conflict scale (DCS); scores < 25 are associated with a persuaded decision while a score > 37.5 implies that one feels unsure about a choice. RESULTS: Between January 1th 2017 and December 31th 2018, 106 patients completed both questionnaires. Before deployment of the 70-GS, 58% of patients (n = 62) formulated a clear treatment preference, of whom 21 patients (34%) changed their opinion on treatment with chemotherapy following the 70-GS. The final decision regarding chemotherapy was in line with the 70-GS result in 90% of patients. The percentage of patients who felt unsure about their preference to be treated with chemotherapy decreased from 42 to 5% after disclosure of the 70-GS. The mean total DCS significantly decreased from pre-test to post-test from 35 to 23, irrespective of the risk estimate (p < 0.001). CONCLUSION: Deployment of the 70-GS changed patients' inclination to undergo adjuvant chemotherapy in one third of patients and decreased patients' decisional conflict.

Mannose binding lectin and prediction of risk for chemotherapy induced febrile neutropenia in patients with a solid tumor.

Mannose-binding lectin (MBL) - deficient patients who undergo chemotherapy for a solid tumor might have an increased risk developing febrile neutropenia (FN). We investigated in a prospective cohort study relations between MBL-serum levels and polymorphisms in MBL promotor genotypes (-550H/L and -221X/Y) on incidence and severity of FN. Risk of FN was 17.9% in MBL-deficient and 22.5% in MBL-sufficient patients (RR = 0.796, p = 0.45). Median MBL serum levels at baseline were respectively 1.39 µg/mL and 1.09 µg/mL (p = 0.92) in patients with and without FN. In conclusion, serum MBL and MBL genotypes (-550H/L and -221X/Y) do not determine the risk for developing FN.

Local treatment in unresectable hepatic metastases of carcinoid tumors: Experiences with hepatic artery embolization and radiofrequency ablation.

BACKGROUND: Hepatic metastases of carcinoid tumors cause incapacitating symptoms, but are usually diffuse and therefore unresectable. In this article we evaluate our experiences with local treatment techniques in the management of carcinoid patients with hepatic metastases and failing systemic treatment. METHODS: Fifteen consecutive carcinoid patients (11 men and 4 women; median age 60 years; range 45-71 years) were treated with either hepatic artery embolization (HAE) with Ivalon particles or radiofrequency ablation (RFA) (percutaneously or intra-operatively). Follow-up evaluation was performed by CT scan and 24-hours urinary 5-HIAA excretions. RESULTS: A total of 18 HAE's was performed in 13 patients, while 10 lesions in 3 patients were treated with RFA. Median follow-up was 12.5 months (2 - 25 months). Median duration of symptoms was 22 months (8 - 193 months). Median overall decrease of 5-HIAA excretion 2 months after HAE was 32% with tumor regression on CT-scan in 4 patients (30%) and improvement of symptoms with a median duration of 15 months in 3 of them (23%). Embolization led to fatal hepatic failure in one patient. The 3 patients treated with RFA showed a decrease of urinary 5-HIAA values of 34, 81 and 93% respectively, with tumor regression in all of them. Improvement of symptoms was reported in 2 patients up to 25 months. CONCLUSION: Liver embolization performed late in the clinical course had limited effect on symptoms and biochemical and radiological parameters. First experiences with RFA are favorable and might encourage to apply RFA more widely in metastatic carcinoid.

Metastatic carcinoid tumors: a clinical review.

Carcinoid tumors are neuroendocrine tumors derived from enterochromaffin cells, which are widely distributed in the body. They can originate from any location in the body, but they are traditionally described as originating from the foregut, midgut, and hindgut. Although the overall incidence of carcinoid tumors appears to have increased in the past decades, the prognosis for patients with metastatic carcinoid tumors has improved during the last decade. Due to longer survival times, complications, such as carcinoid heart disease, and new metastatic patterns, like skin and bone metastases, may become more important features of carcinoid disease. Therapy focused on these complications should be part of the management. Combining new diagnostic and treatment modalities in metastatic carcinoid patients may result in better quality of life and longer survival times. The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach, with decisions made in multidisciplinary meetings focused on "tailor-made" therapy based on patients' specific conditions. Because carcinoid tumors are uncommon, effort should be made to treat these patients in specialized centers and for these centers to join together in multicenter studies.

Daily cyclic changes in the urinary excretion of 5-hydroxyindoleacetic acid in patients with carcinoid tumors.

BACKGROUND: Vasoactive peptides produced by neuroendocrine tumors can induce characteristic symptoms of the carcinoid syndrome (flushing, diarrhea, and wheezing). To what extent external factors provoke these symptoms and how excretion of 5-hydroxyindoleacetic acid (5-HIAA), the degradation product of serotonin, varies throughout the day remain unknown. In this study, we investigated whether symptoms and daily activity are related to 5-HIAA excretion and whether 24-h urine collection is needed. METHODS: In 26 patients with metastatic carcinoid (14 men and 12 women; median age, 60 years) urine was collected in portions of 4 or 8 h during 2 days. Patients were asked to keep a diary in which they noted symptoms of flushes, consistency of stools, activities, and food intake. RESULTS: Excretion of 5-HIAA in 24-h urine was increased in 88% of the patients (median, 515 micromol/24 h). Overnight-collected urine appeared the most representative for 24-h collection concentrations (correlation coefficient = 0.81). We found no clear correlation between symptoms of the carcinoid syndrome and degree of activity. Watery diarrhea was reported only by patients with strong variations in 5-HIAA excretion. One-half of the patients (n = 16) exhibited a high variability in urinary 5-HIAA excretion throughout the day, with increased concentrations most prominent in morning collections (P = 0.0074) and lower concentrations in the evening (P = 0.0034). In the other patients these curves were flat. CONCLUSIONS: Cyclic changes in patients relate to high variability in 5-HIAA excretion. Overnight-collected urine can replace the 24-h urine collection, and marked variations in 5-HIAA excretion seem to be associated with severity of diarrhea.

Carcinoid heart disease: the role of urinary 5-hydroxyindoleacetic acid excretion and plasma levels of atrial natriuretic peptide, transforming growth factor-beta and fibroblast growth factor.

BACKGROUND: Serotonin excretion plays a role in the development of carcinoid heart disease (CHD), but the exact pathogenesis is not known. In the current study, the authors evaluated 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion, as well as plasma levels of transforming growth factor-beta (TGF-beta), fibroblast growth factor (FGF), and atrial natriuretic peptide (ANP) in patients with and without CHD determined by ultrasound examination. METHODS: Urine and plasma samples were obtained for 37 patients and cardiac ultrasound was performed during follow-up in 1999 and 2000. Median 5-HIAA excretion was calculated for the period between diagnosis and ultrasound examination. CHD was defined as the thickening of the tricuspid valve with additional III-IV/IV tricuspid valve regurgitation. RESULTS: CHD was found in 9 of 37 patients (24%). No significant differences were found for age, gender, presence, and duration of liver metastases. All CHD patients had symptoms of the carcinoid syndrome compared with 71% of the non-CHD patients (P = 0.159). Median 5-HIAA excretion was significantly higher in the CHD group compared with the non-CHD group: 576 micromol/24 hours versus 233 micromol/24 hours (P = 0.02). No difference in TGF-beta and FGF plasma levels was observed between both groups (P = 0.139 and P = 0.985, respectively), nor was there a correlation with morphology of the tricuspid valve or degree of dilatation of the right atrium/ventricle. However, the CHD group had higher median ANP levels than the non-CHD group: 48 ng/L and 25 ng/L, respectively (P = 0.026). CONCLUSIONS: High levels of 5-HIAA excretion and plasma ANP were found to be associated with CHD. No significant relation with TGF-beta or FGF was been found.