Summary
Purpose
To date, it is not clear which anticancer agent is useful in combination with trastuzumab and pertuzumab As the first and second selective regimens for advanced or metastatic breast ...cancer (AMBC), this multicenter, open-label, phase II trial (JBCRG-M03: UMIN000012232) presents a prespecified analysis of eribulin in combination with pertuzumab and trastuzumab.
Methods
We enrolled 50 patients with no or single prior chemotherapy for HER2-positive AMBC during November 2013–April 2016. All patients received adjuvant or first-line chemotherapy with trastuzumab and a taxane. The treatment comprised eribulin on days 1 and 8 of a 21-day cycle and trastuzumabplus pertuzumab once every 3 weeks, all administered intravenously. While the primary endpoint was the progression-free survival (PFS), secondary endpoints were the response rate and safety.
Results
Of 50 patients, 49 were eligible for safety analysis, and the full analysis set (FAS) included 46 patients. We treated 8 (16%) and 41 (84%) patients in first- and second-line settings, respectively. While 11 patients (23.9%) had advanced disease, 35 (76.1%) had metastatic disease. The median PFS was 9.2 months for all patients 95% confidence interval (CI): 7.0–11.4. In the FAS, 44 patients had the measurable lesions and the complete response rate (CR) was 17.4%, and partial response rate (PR) was 43.5%. The grade 3/4 adverse events were neutropenia (5 patients, 10.2%), including febrile neutropenia (2 patients, 4.1%), hypertension (3 patients, 6.1%), and other (1 patient). The average of the left ventricular ejection fraction did not decline markedly. No symptomatic left ventricular systolic dysfunction was observed.
Conclusions
In patients with HER2-positive AMBC, eribulin, pertuzumab, and trastuzumab combination therapy exhibited substantial antitumor activity with an acceptable safety profile. Hence, we have started a randomized phase III study comparing eribulin and a taxane in combination with pertuzumab and trastuzumab for the treatment of HER2-positive AMBC.
Trial registration ID:
UMIN-CTR: UMIN000012232.
mutations in breast cancer are one of the mechanisms of resistance to aromatase inhibitors. These mutations are common in metastatic breast cancer; however, these are rare in primary breast cancer. ...However, these data have been analyzed mainly in formalin-fixed, paraffin-embedded tissue; thus, rare mutations that may be present in primary breast cancer may be overlooked. In this study, we developed a highly sensitive mutation detection method called locked nucleic acid (LNA)-clamp droplet digital PCR (ddPCR) and validated it. The mutation detection sensitivity was substantiated to 0.003%. Then, we used this method to analyze
mutations in fresh-frozen (FF) tissues of primary breast cancer. cDNA extracted from the FF tissues of 212 patients with primary breast cancers were measured. Twenty-eight
mutations were found in twenty-seven (12.7%) patients. Sixteen (7.5%) patients had Y537S mutations and twelve (5.7%) had D538G mutations. Two mutations with a variant allele frequency (VAF) of ≥0.1% and twenty-six mutations with a VAF of <0.1% were found. By using this LNA-clamp ddPCR, this study demonstrated the presence of minor clones with a VAF of <0.1% in primary breast cancer.
We attempted to detect circulating tumor DNA (ctDNA), taking advantage of molecular barcode next-generation sequencing (MB-NGS), which can be more easily customized to detect a variety of mutations ...with a high sensitivity than PCR-based methods. Sequencing with a gene panel consisting of the 13 most frequently mutated genes in breast tumors from stage I or II patients revealed 95 somatic mutations in the 12 genes in 62% (62/100) of tumors. Then, plasma DNA from each patient (n = 62) before surgery was analyzed via MB-NGS customized to each somatic mutation, resulting in the detection of ctDNA in 16.1% (10/62) of patients. ctDNA was significantly associated with biologically aggressive phenotypes, including large tumor size (P = .004), positive lymph node (P = .009), high histological grade (P < .001), negative ER (P = .018), negative PR (P = .017), and positive HER2 (P = .046). Furthermore, distant disease-free survival was significantly worse in patients with ctDNA (n = 10) than those without ctDNA (n = 52) (P < .001). Our results demonstrate that MB-NGS personalized to each mutation can detect ctDNA with a high sensitivity in early breast cancer patients at diagnosis, and it seems to have a potential to serve as a clinically useful tumor marker for predicting their prognosis.
Background
This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule.
Methods
Patients with metastatic ...breast cancer (MBC) treated with both anthracycline and taxane and ≤ 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m
2
on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m
2
on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated.
Results
Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events.
Conclusion
This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule.
Clinical trial registration
University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491).
We previously reported the synergistic effect of S-1 and eribulin in preclinical models. In addition, our phase I study revealed the recommended dose for the phase II study of the combination therapy ...in advanced breast cancer (ABC) patients pre-treated with anthracycline and taxane. Our current study reports on the efficacy and safety of the combined use of eribulin and S-1 in patients with ABC and poor prognosis.
Patients with breast cancer who received prior anthracycline- and/or taxane-based therapy were assigned to receive a combination therapy of eribulin (1.4 mg/m
on days 1 and 8, every 21 days) and S-1 (65 mg/m
, on days 1 to 14, every 21 days) for advanced/metastatic disease. All patients had at least one clinicopathological factor such as being oestrogen receptor negative, Human Epidermal Growth Factor Receptor 2 (HER2) receptor negative, presence of visceral involvement, presence of three or more metastatic sites, or having a disease-free interval shorter than 2 years. The primary endpoint was the independent-reviewer assessed objective response rate (ORR). Secondary endpoints were clinical benefit rate, disease control rate, progression-free survival (PFS), and overall survival (OS).
This study enrolled 33 patients. Confirmed ORR was 33.3% (95% CI: 17.3 to 52.8). Median PFS was 7.5 months (95% CI: 4.0 to 14.3). Median OS time was not reached during the current experimental periods. The most common grade 3/4 adverse event was neutropenia (68.8%).
The combination of eribulin and S-1 is safe and effective for treatment in patients with ABC and poor prognosis.
Current Controlled Trials UMIN000015049 , date of registration: September 5th 2014.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Paclitaxel (PTX) is an essential anticancer drug used to treat breast cancer. Because it contains alcohol as a solvent, it is contraindicated in many Japanese breast cancer patients when ...they are suspected of alcohol intolerance. Aldehyde dehydrogenase 2 (ALDH2) is one of several enzymes that catalyzes dehydrogenation of aldehydes, and plays an important role in ethanol metabolism. Deficiency of this isozyme is believed to be responsible for facial flushing and other unpleasant symptoms following ethanol intake. In this study, we examined the safety of PTX for patients with the ALDH2 GA genotype.
Methods
We performed ALDH2 genotyping on 25 patients with various cancers who were suspected to be intolerant to alcohol based on an interview using a simple question. Ten patients with the ALDH2 GA genotype, including 5 breast cancer patients, underwent chemotherapy containing PTX up to 100 mg/m
2
(range 80–100 mg/m
2
), and were questioned about 16 alcohol-related symptoms at 11 timepoints to evaluate sensitivity to alcohol.
Results
All patients completed the first course of planned chemotherapy with either no or grade 1 alcohol-related symptoms.
Conclusions
Our study suggests that PTX up to 100 mg/m
2
can be used safely for patients with the ALDH2 GA genotype. To confirm the necessity of a genotyping test for ALDH2, further studies evaluating alcohol sensitivity in response to PTX among patients with the ALDH2 AA genotype are required.
Optimal treatment strategies for hormone receptor (HR)-positive, HER2-negative advanced and/or metastatic breast cancer (AMBC) remain uncertain. We investigated the clinical usefulness of adding ...capecitabine to maintenance endocrine therapy after induction chemotherapy and the efficacy of reinduction chemotherapy. Patients who had received bevacizumab–paclitaxel induction therapy and did not have progressive disease (PD) were randomized to maintenance therapy with endocrine therapy alone (group E) or endocrine plus capecitabine (1657 mg/m2/day on days 1–21, q4w) (group EC). In case of PD after maintenance therapy, patients received bevacizumab–paclitaxel reinduction therapy. Ninety patients were randomized. The median progression-free survival (PFS) under maintenance therapy (primary endpoint) was significantly longer in group EC (11.1 {95% CI, 8.0–11.8} months) than in group E (4.3 {3.6–6.0} months) (hazard ratio, 0.53; p < 0.01). At 24 months from the induction therapy start, the overall survival (OS) was significantly longer in group EC than in group E (hazard ratio, 0.41; p = 0.046). No difference was found in the time to failure of strategy (13.9 and 16.6 months in groups E and EC, respectively). Increased capecitabine-associated toxicities in group EC were tolerable. Addition of capecitabine to maintenance endocrine therapy may be a beneficial option after induction chemotherapy for HR-positive, HER2-negative AMBC patients.
The PRECIOUS study (UMIN000018202) is being conducted as a multicenter, randomized, open-label Phase III study to determine if retreatment with pertuzumab is more effective than conventional ...treatment in HER2-positive locally advanced (LA)/metastatic breast cancer (MBC) patients previously treated with pertuzumab, trastuzumab and chemotherapy. Patients are randomized 1:1 into chemotherapy plus trastuzumab with or without pertuzumab groups. The latest regimen before enrollment did not include pertuzumab, and the number of previous chemotherapy regimens for LA/MBC did not exceed three. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include independent reviewer-assessed progression-free survival, progression-free survival in patients treated with trastuzumab emtansine as the latest regimen, response rate, response duration, overall survival, safety and health-related quality of life. Target accrual is 370 patients, allowing the observation of 325 events, yielding an 80% power for detection of a hazard ratio of 0.739 with a one-sided 5% level of significance.
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