Treatment of HER-2 positive breast cancer

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Taxane-containing chemotherapy in the treatment of early breast cancer patients

In primary breast cancer, taxane-based compared with anthracycline-based adjuvant chemotherapy significantly reduces the relative risk of recurrence (ranging from 17% to 36%) and sometimes improves overall survival. Different dosages and schedules of anthracyclines and taxanes have been tested. Randomized studies comparing sequential versus concurrent administrations are in progress and no data about efficacy are available. However, based on a single randomized trial and on indirect comparisons, safety and tolerability seem to be better with sequential schema. A formal comparison between weekly and every 3 weeks administration of taxanes reported no substantial difference in terms of efficacy. However, taking into account a subgroup analysis of this study, and results coming from metastatic disease, the best way to give taxanes seems to be either weekly paclitaxel or docetaxel every 3 weeks. In the majority of the study, taxane efficacy seems to be independent of hormonal receptor status, i.e. active in both hormonal receptor positive and negative disease. In conclusion, taxane-based adjuvant chemotherapy is a standard option for most early breast cancer patients with node-positive disease. No sufficient and dedicated data are available in node-negative disease

The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients

Background: Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials. Methods/design: This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year. Discussion: A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC. Trial registration: EudraCT Number: 2015–004824-77; ClinicalTrial.gov Identifier: NCT03047837. Registered on February 1, 2017

Precision fluoropyrimidines dosing in a compound heterozygous variant carrier of the DPYD gene: a case report

Background: Fluoropyrimidines (FPs) form still nowadays the backbone of chemotherapic schemes in colorectal cancer (CRC). Inter-patient variability of the toxicity profile of FPs may be partially accounted for by variable expression of dihydropyrimidine dehydrogenase (DPD). DPD rate activity is genetically determined by its extremely polymorphic coding gene DPYD. In spite of pharmacogenetic guideline-directed-dosing of FPs based regimens treating carrier of multiple variants of DPYD gene remains still challenging. Case presentation: We present a case of a 48-year-old Caucasian man, compound heterozygous variant carrier of the DPYD gene (HapB3 and c.2194G>A) who had a diagnosis of adenocarcinoma of the left colon and was safely treated with a pharmacogenetic-guided 25% dose reduction of the standard CAP adjuvant treatment. Compound heterozygosis may have been responsible for an earlier over exposure to CAP resulting into low-grade toxicity with an anticipated median time to toxicity of the c.2194G>A variant to the 4th vs. 6th cycles. Some haplotypes of DPYD variants may have an advantage in terms of survival compared to wild-type patients. Our patient may also have benefitted from compound heterozygosis, as shown by no evidence of disease (NED) at 6-month follow-up. Conclusion: Pharmacogenetic-guided dosing of DPYD intermediate metabolizer compound heterozygous HapB3 and c.2194G>A variant carries should be managed by a multidisciplinary team with a dose reduction ranging from 25 to 50% to maintain effectiveness and close clinical monitoring for early detection of ADRs

Pegfilgrastim administration after 24 or 72 or 96 h to allow dose-dense anthracycline- and taxane-based chemotherapy in breast cancer patients: a single-center experience within the GIM2 randomized phase III trial

To evaluate the safest timing of pegfilgrastim administration in dose-dense anthracycline- and taxane-based chemotherapy, three different cohorts of patients enrolled in the Gruppo Italiano Mammella (GIM) 2 study and treated at the coordinating center received pegfilgrastim 24 h (cohort A) or 72 h (cohort B) or 96 h (cohort C) after chemotherapy. A total of 41 patients were included. The safety of pegfilgrastim administration in terms of occurrence of early and late leukocytosis and the behavior of white blood cells (WBC) counts in the three cohorts across all chemotherapy cycles were evaluated. Anthracycline and taxane cycles were analyzed separately. The occurrence of early leukocytosis was a more common event in patients in cohort A in both anthracycline and taxane cycles (75 and 66.7 %) as compared to cohort B (50 and 60 %) and cohort C (66.7 and 33.3 %). More patients in cohort C developed late leukocytosis in both anthracycline and taxane cycles (50 and 100 %) as compared to cohort A (0 and 66.7 %) and cohort B (35.7 and 86.7 %). Patients in cohort A experienced the highest median value of WBC count 24 h after pegfilgrastim administration in both anthracycline and taxane cycles (61.2 x 10(3)/mu l and 67.8 x 10(3)/mu l). Patients in cohort C experienced the highest median value of WBC count at day 13 in both anthracycline and taxane cycles (19.4 x 10(3)/mu l and 24.2 x 10(3)/mu l). For the prevention of leukocytosis, the safest timing of pegfilgrastim administration based on WBC count in dose-dense anthracycline- and taxane-based regimens seems to be 72 h after chemotherapy