Abstract
Background: Adjuvant chemotherapy combining anthracyclines and taxanes for early stage breast cancer (ESBC) have demonstrated disease-free survival (DFS) and overall survival (OS) benefits. ...Among the 3rd generation regimens, 2 options have been favoured: FEC-Docetaxel (FECD) and AC-Paclitaxel (ACT). ACT may be delivered with dose-dense (ddACT) or weekly taxane scheduling (ddACWT), compared to traditional every 3-weekly (q3ACT) scheduling. Despite literature supporting both FECD and (dd)ACT regimens in the management of ESBC, no direct prospective trial has evaluated their comparative effectiveness.
Methods: A retrospective review of the BC Cancer Breast Cancer Outcomes Unit (BCOU) and the Alberta Health Services (AHS) databases was performed to identify patients with HER2 negative, stage 1-3 ESBC, who received adjuvant chemotherapy between 2007-2014. The primary endpoint was OS and the secondary endpoint was RFS, defined as freedom from local (invasive), regional or distant recurrence or breast cancer death. Outcome comparisons were made between FECD, ddACT/ddACWT and q3ACT using the Kaplan Meier method. Treatment arms were compared using a log-rank test for univariate analysis. A multivariate analysis was also conducted for OS comprising age, stage, grade, receptor status and type of chemotherapy received (FECD vs combined ACT group).
Results: A total of 4047 patients met inclusion criteria, including 2685 FECD, 1259 ddACT and 103 ACT. Median age was 53 (24-77) in the FECD group vs 52 (26-68) in the ddACT/ddACWT group and 58 (43-78) in the q3ACT group. The majority had stage 2 disease, 51.3%, 53.5% and 50.5% in the FECD, ddACT/ddACWT and q3ACT groups, respectively. Most were HR+, 84.5% in the FECD group vs 66.9% in both the ddACT/ddACWT and q3ACT groups. In the FECD group, 42.8% had a grade 2 tumour and 48.2% a grade 3 tumour vs 35.4% and 56.4% in the ddACT/ddACWT group and 35.0% and 58.3% in the q3ACT group. Lymphovascular invasion (LVI) was present in 40.7% of patients who received FECD vs 39.7% for ddACT/ddACWT and 26.2% for ACT. 5-year OS, for the FECD group was 90.3% (95%CI 89.1,91.4) vs 87.0% (95%CI 84.3,89.2) for the ddACT/ddACWT and 84.9% (95%CI 75.5,90.8) for the q3ACT groups, p=0.0907. 5-year RFS was 85.5% (95%CI 84.0-86.8) with FECD vs 84.4% (95% 81.9,86.6) for ddACT/ddACWT and 87.7% (95%CI 79.2,92.8) with q3ACT,p=0.4200. In multivariate analysis: age, stage and grade were significantly associated with OS whereas type of chemotherapy received (FECD vs ACT) was not (p=0.165). Finally, OS rates were compared across provinces and no significant differences were identified, 87.0% vs 88.0% (p=0.6294). Subgroup analyses by receptor type, comparing HR+ and TNBC are ongoing.
Conclusions: The use of FECD as compared to ACT based chemotherapy did not reveal significant differences in OS or RFS in this population-based study. Further, chemotherapy regimen was not associated with differences in overall survival, as compared to other well recognized prognostic factors. While the results were obtained from a retrospective analysis, conclusive prospective data is lacking. These results may therefore reassure physicians and patients alike on a comparable efficacy of these regimens in a real-life setting.
Citation Format: LeVasseur N, Veitch Z, Diocee RM, Gondara L, Cheung W, Khan O, Cossetti R, Gelmon KA, King K, Lupichuk S, Chia SK, Tang P, Simmons C. Real world outcomes of adjuvant FECD, ddACT and ACT for the treatment of early stage breast cancer - A multicenter retrospective analysis abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-02.
Background: Young women with breast cancer (YWBC) have unique survivorship needs because of life stage, and interventions to address these are limited. We aimed to understand the unmet needs of YWBC ...to develop a tailored self-management tool to improve breast cancer experience and psychosocial-sexual outcomes for YWBC in the long term. Methods: We conducted semistructured survivor and clinical interviews. Purposive maximum variation sampling was used. Inclusion criteria were women 40 years of age or younger at diagnosis, who had stage 0-IV disease, with a minimum of 1 year after diagnosis and active treatment complete. Interviews were recorded and transcribed, using collaborative group immersion to analyze data and identify emerging themes. Results: Thirty-four participants were interviewed from 10 centres across 7 Canadian provinces. Participantreported demographic characteristics were as follows: 18% were members of a visible minority, 9% were born outside Canada, 7% were Indigenous and 54% of patients household income was at or below the Canadian average. Thirty-six percent received neoadjuvant chemotherapy, 47% underwent mastectomy with reconstruction and 41% underwent contralateral prophylactic mastectomy. The YWBC who were interviewed reported psychological, self-identity, fertility and sexual health needs, which have a substantial impact on intimacy in relationships. Partner fear and anxiety were described, without professional or social support measures. Education on psychology, sexual health and peer mentorship were suggested to improve self-support. Conclusion: We have identified unique psychosocial-sexual needs among this young cohort of women. We will target these through a novel and pragmatic selfmanagement tool, to be used across Canada, aiming to improve YWBCs experience and long-term morbidity.
Lentiviral vectors efficiently transduce human CD34+ cells that mediate long‐term engraftment of nonobese diabetic/severe combined immunodeficient mice. However, hematopoiesis in these animals is ...abnormal. Typically, 95% of the human cells in peripheral blood are B lymphocytes. To determine whether lentiviral vectors efficiently transduce stem cells that maintain normal hematopoiesis in vivo, we isolated Sca‐1+c‐Kit+Lin− bone marrow cells from mice without 5‐fluorouracil treatment, and transduced these cells in the absence of cytokine stimulation with a novel lentiviral vector containing a GFP (green flourescent protein) reporter gene. These cells were transplanted into lethally irradiated C57Bl/6 mice. In fully reconstituted animals, GFP expression was observed in 8.0% of peripheral blood mononuclear cells for 20 weeks posttransplantation. Lineage analysis demonstrated that a similar percentage (approximately 8.0%) of GFP‐positive cells was detected in peripheral blood B cells, T cells, granulocytes and monocytes, bone marrow erythroid precursor cells, splenic B cells, and thymic T cells. In secondary transplant recipients, up to 20% of some lineages expressed GFP. Our results suggest that quiescent, hematopoietic stem cells are efficiently transduced by lentiviral vectors without impairing self‐renewal and normal lineage specification in vivo. Efficient gene delivery into murine stem cells with lentiviral vectors will allow direct tests of genetic therapies in mouse models of hematopoietic diseases such as sickle cell anemia and thalassemia, in which corrected cells may have a selective survival advantage.
Abstract
Supported by a PHRC grant (#09-18-005)
Background: Recent literature has suggested that germline genetic variants of drug-metabolizing enzymes or CYP19A1 (coding for aromatase) may be ...involved in the systemic aromatase inhibitors (AI) concentrations or the occurrence of side effects (Hertz et al. Pharmacogenomics 2017). A prospective multicentre 3-year follow-up study was carried out to investigate the relationships between pharmacogenetics (PG), pharmacokinetics (PK) and toxicity in breast cancer patients treated with adjuvant AI (n=1098) or tamoxifen (n=879). The clinical results and the tamoxifen PG/PK analyses are described elsewhere (abstracts #851544 and #850248).
Methods: SNP genotyping of 95 SNPs was performed on the Biomark (Fluidigm) with Taqman assays and was available for 373, 515 and 151 patients treated with anastrozole (ANA), letrozole (LETRO) and exemestane (EXE) respectively. CYP2A6 metaboliser status (MS) (poor, intermediate or normal) was determined based on alleles function (*1, *9, *2) and number of CYP2A6 copies. Trough plasma concentrations of each drug were determined 6 months after the start of the study by UPLC-MS/MS and were available for 342, 463 and 130 patients of the ANA, LETRO and EXE arms. Patients with AI concentrations below the limit of quantification were excluded for non-compliance (9 patients for ANA, 8 patients for LETRO and 7 patients for EXE). Toxicity was measured as a binary outcome (occurrence or worsening of hot flushes, fatigue, pain, arthralgia, vaginal dryness). All genetic associations were adjusted for multiple testing.
Results: ANA concentration was significantly higher in patients experiencing pain (p=0.025) and was associated with rs28365063 (UGT2B7 g.372A>G).
LETRO concentrations were strongly associated with CYP2A6 metabolizer status (p=0.0001) but did not differ in patients with or without toxicity.
In the EXE arm, patients with hot flushes or arthralgia had a significantly lower level of exemestane (p= 0.0002 and p=0.023 respectively) but since the metabolism of EXE leads to active 17-hydroexemestane, we can hypothesize that the lower EXE concentration is an indirect reflection of the metabolite formation. A SNP (rs2307424) in NR1I3 gene (coding for the constitutive androstane receptor CAR) was associated with EXE concentrations. CAR has been shown to regulate CYP2B6, which is involved in the formation of 6-hydroxy-methyl-exemestane (inactive metabolite).
Regarding the relationships between PG and toxicity, in the ANA arm, 3 SNPs of CYP19A1 gene tended to be associated with hot flushes worsening (rs934635) and arthralgia (rs10046 and rs2304463) but did not remain significant after multiple tests correction. In the EXE arm, several SNPs in NR1I3 gene were associated with fatigue.
In the LETRO arm, patients with a poor CYP2A6 MS had a higher risk of experiencing depression.
Conclusions: Our study confirms the predominant role of CYP2A6 in LETRO PK. To our knowledge, this is the first study to report on the role of UGT2B7 rs28365063 in ANA and NR1I3 in EXE PK and side effects. These relationships need to be re-evaluated with the drug concentrations obtained during the 3-year follow-up.
Citation Format: Thomas F, Marquet P, Pinguet F, White-Koning M, Robert J, Tafzi N, Solassol I, Despax R, Levasseur N, Ellis S, Massoubre A, Mbatchi L, Le Morvan V, Roché H, Chatelut E, Evrard A. Pharmacogenetic determinants of aromatase inhibitors pharmacokinetics and side effects: 6-month results of the adjuvant breast cancer longitudinal PHACS study (NCT01127295) 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 P3-12-07.
Until recently, the use of neoadjuvant endocrine therapy was mainly restricted to those patients whose general frailty or comorbidities were contraindications to surgery. There is now increased ...evidence that certain patient populations (i.e. older patients with hormone-receptor positive disease) can gain as good a pathologic response, with considerably less toxicity, from neoadjuvant endocrine therapy than from neoadjuvant chemotherapy. Optimization of neoadjuvant endocrine therapy is therefore an important therapeutic goal. However, possibly of greater importance in the overall management of breast cancer, is the increased interest in exploring the effects of brief periods of endocrine therapy on in vivo biomarkers, in so called window of opportunity trials. These trials can not only be used to identify the mechanisms of action of novel agents but also to predict optimal subsequent adjuvant therapy for individual patients. While this paper will briefly review the history of neoadjuvant endocrine therapy, more emphasis will be on the evaluation of pivotal window of opportunity trials that will likely lead to a long awaited paradigm shift in the management of breast cancer.
Sickle cell disease (SCD) and Beta thalassemia are disorders of beta globin production and function that lead to severe anemia and significant disease complications across a multitude of organ ...systems. Autologous transplantation of hematopoietic stem cells engineered through the upregulation of fetal hemoglobin (HbF) or correction of the beta globin gene have the potential to reduce disease burden in patients with beta hemoglobinopathies. Base editing is a recently developed technology that enables precise modification of the genome without the introduction of double strand DNA breaks.
Gamma globin gene promoters were comprehensively screened with cytosine and adenine base editors (ABE) for the identification of alterations that would derepress HbF. Three regions were identified that significantly upregulated HbF, and the most effective nucleotide residue conversions are supported by natural variation seen in patients with hereditary persistence of fetal hemoglobin (HPFH). ABEs have been developed that significantly increase the level of HbF following nucleotide conversion at key regulatory motifs within the HBG1 and HBG2 promoters. CD34+ hematopoietic stem and progenitor cells (HSPC) were purified at clinical scale and edited using a process designed to preserve self-renewal capacity. Editing at two independent sites with different ABEs reached 94 percent and resulted in up to 63 percent gamma globin by UPLC. The levels of HbF observed should afford protection to the majority of SCD and Beta thalassemia patients based on clinical observations of HPFH and non-interventional therapy that links higher HbF dosage with milder disease (Ngo et al, 2011 Brit J Hem; Musallam et al, 2012 Blood).
Directly correcting the Glu6Val mutation of SCD has been a recent goal of genetic therapies designed for the SCD population. Current base editing technology cannot yet convert mutations like those that result from the A-T transversion in sickle beta globin; however, ABE variants have been designed to recognize and edit the opposite stranded adenine residue of valine. This results in the conversion of valine to alanine and the production of a naturally occurring variant known as Hb G-Makassar. Beta globin with alanine at this position does not contribute to polymer formation, and patients with Hb G-Makassar present with normal hematological parameters and red blood cell morphology. SCD patient fibroblasts edited with these ABE variants achieve up to 70 percent conversion of the target adenine. CD34 cells from healthy donors were then edited with a lead ABE variant, targeting a synonymous mutation in an adjacent proline that resides within the editing window and serves as a proxy for editing the SCD mutation. The average editing frequency was 40 percent. Donor myeloid chimerism documented at these levels in the allogeneic transplant setting exceeds the 20 percent that is required for reversing the sickle phenotype (Fitzhugh et al, 2017 Blood).
These next generation editing approaches provide a promising new modality for treating patients with Beta thalassemia and SCD.
No relevant conflicts of interest to declare.
Hyaluronan (HA) has different biological functions according to its molar mass; short HA fragments are involved in inflammation processes and angiogenesis, whereas native HA is not. ...Physicochemically, studies of native HA hydrolysis catalyzed by bovine testicular hyaluronidase (HAase) have suggested that kinetic parameters depend on HA chain length. To study the influence of HA chain length in more detail, and to try to correlate the physicochemical and biological properties of HA, HA hydrolysis catalyzed by HAase was used in a new procedure to obtain HA fragments of different molar masses. HA fragments (10-mg scale) with a molar mass from 800 to 300,000
g
mol
−1 were prepared, purified using low-pressure size exclusion chromatography (SEC), lyophilized, and characterized in molar mass by either mass spectrometry or HPLC–SEC–multiangle laser light scattering. The polydispersity index of the purified fractions was less than 1.25. The complete set of HA standards obtained was used to calibrate our routine HPLC–SEC device using only a refractive index (RI) detector. We showed that the
N-acetyl-
d-glucosamine reducing end assay and the calibrated HPLC–SEC–RI gave equivalent kinetic data. In addition, the HPLC–SEC–RI furnished the mass distribution of the polysaccharide during its hydrolysis.
Hyaluronidase (HAase) plays an important role in the control of the size and concentration of hyaluronan (HA) chains, whose biological properties strongly depend on their length. Our previous studies ...of HA hydrolysis catalyzed by testicular HAase demonstrated that, whilst the substrate–dependence curve has a Michaelis–Menten shape with a 0.15 mol L
−
1
ionic strength, at low ionic strength (5 mmol L
−
1
), a strong decrease in the initial hydrolysis rate is observed at high substrate concentrations; the HA concentration for which the initial rate is maximum increases when the HAase concentration is increased. After examination of various hypotheses, we suggested that this could be explained by the ability of HA to form non-specific complexes with HAase, which thus becomes unable to catalyze HA hydrolysis. In order to verify this hypothesis, we first showed from turbidimetric measurements that HAase, like albumin, is able to form electrostatic complexes with HA. Albumin then was used as a non-catalytic protein able to compete with HAase for the formation of non-specific complexes with HA, allowing HAase to be free and catalytically active. The kinetic results showed that the HA–HAase non-specific complex inhibits HAase catalytic activity towards HA. Depending on the albumin concentration with respect to the HAase and HA concentrations, albumin can either remove this inhibition or induce another type of inhibition. Finally, the extent of such non-specific interactions between polyelectrolytes and proteins in HAase inhibition or activation, in particular under
in vivo conditions, is discussed.
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