Improved survival for sequentially as opposed to concurrently delivered neoadjuvant chemotherapy in non-metastatic breast cancer

Purpose

Although breast cancer in young women accounts for <10% of diagnoses annually, tumors in young patients exhibit more aggressive characteristics and higher mortality rates. Determination of the frequency of germline mutations in cancer predisposition genes is needed to improve the understanding of breast cancer etiology in young women.

Methods

All female patients enrolled in the Clinical Breast Cancer Project between 2001 and 2015 and diagnosed with invasive breast cancer before age 40 were included in this study. Family history was classified using the NCCN Familial Risk Assessment guidelines. Targeted sequencing of 94 cancer predisposition genes was performed using peripheral blood DNA. Variants were detected using VariantStudio and classified using ClinVar.

Results

Seven percent (141/1980) of patients were young women and 44 had a significant family history. Sequencing was completed for 118 women with genomic DNA. Pathogenic mutations were present in 27 patients: BRCA1 (n = 10), BRCA2 (n = 12), TP53 (n = 1), and CHEK2 (n = 4). Mutations classified as pathogenic were also detected in APC (n = 1) and MUTYH (n = 2). Variants of uncertain significance (VUS) were detected in an additional 17 patients in ten genes.

Discussion

Pathogenic mutations in high- and moderate-risk breast cancer genes were detected in 23% of young women with an additional 3% having pathogenic mutations in colon cancer predisposition genes. VUS were observed in 14% of women in genes such as ATM, BRCA2, CDH1, CHEK2, and PALB2. Identification of those non-genetic factors is critical to reduce the burden of breast cancer in this population.

     

<Emphasis Type="Italic">BRCA1</Emphasis> mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD

Purpose

The aim of this study was to determine whether BRCA1/2 mutation carriers produce fewer mature oocytes after ovarian stimulation for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), in comparison to a PGD control group.

Methods

A retrospective, international, multicenter cohort study was performed on data of first PGD cycles performed between January 2006 and September 2015. Data were extracted from medical files. The study was performed in one PGD center and three affiliated IVF centers in the Netherlands and one PGD center in Belgium. Exposed couples underwent PGD because of a pathogenic BRCA1/2 mutation, controls for other monogenic conditions. Only couples treated in a long gonadotropin-releasing hormone (GnRH) agonist-suppressive protocol, stimulated with at least 150 IU follicle stimulating hormone (FSH), were included. Women suspected to have a diminished ovarian reserve status due to chemotherapy, auto-immune disorders, or genetic conditions (other than BRCA1/2 mutations) were excluded. A total of 106 BRCA1/2 mutation carriers underwent PGD in this period, of which 43 (20 BRCA1 and 23 BRCA2 mutation carriers) met the inclusion criteria. They were compared to 174 controls selected by frequency matching.

Results

Thirty-eight BRCA1/2 mutation carriers (18 BRCA1 and 20 BRCA2 mutation carriers) and 154 controls proceeded to oocyte pickup. The median number of mature oocytes was 7.0 (interquartile range (IQR) 4.0–9.0) in the BRCA group as a whole, 6.5 (IQR 4.0–8.0) in BRCA1 mutation carriers, 7.5 (IQR 5.5–9.0) in BRCA2 mutation carriers, and 8.0 (IQR 6.0–11.0) in controls. Multiple linear regression analysis with the number of mature oocytes as a dependent variable and adjustment for treatment center, female age, female body mass index (BMI), type of gonadotropin used, and the total dose of gonadotropins administered revealed a significantly lower yield of mature oocytes in the BRCA group as compared to controls (p = 0.04). This finding could be fully accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50).

Conclusions

Ovarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserve.

     

A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy

Increased activation of the PI3K/Akt/mTOR pathway is a common factor in putative mechanisms of trastuzumab resistance, resulting in dysregulation of cell migration, growth, proliferation, and survival. Data from preclinical and phase 1/2 clinical studies suggest that adding everolimus (an oral mTOR inhibitor) to trastuzumab plus chemotherapy may enhance the efficacy of, and restore sensitivity to, trastuzumab-based therapy. In this phase 2 multicenter study, adult patients with HER2-positive advanced breast cancer resistant to trastuzumab and pretreated with a taxane received everolimus 10 mg/day in combination with paclitaxel (80 mg/m² days 1, 8, and 15 every 4 weeks) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), administered in 28-day cycles. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients were enrolled; one remained on study treatment at the time of data cutoff. The median number of prior chemotherapy lines for advanced disease was 3.5 (range 1–11). The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99–7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85–24.11 months). Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4). Nonhematologic grade 3/4 AEs included stomatitis (20.0 %), diarrhea (5.5 %), vomiting (5.5 %), fatigue (5.5 %), and pneumonia (5.5 %), all grade 3. These findings suggest that the combination of everolimus plus trastuzumab and paclitaxel is feasible, with promising activity in patients with highly resistant HER2-positive advanced breast cancer. This combination is currently under investigation in the BOLERO-1 phase 3 trial.     

Implementation of sentinel node biopsy in breast cancer patients in the Netherlands

BackgroundThis population-based study describes the implementation of the sentinel node biopsy (SNB) in breast cancer patients in the Netherlands. We examined the extent of use over time of SNB in women who were considered eligible for SNB on the basis of their clinical status.MethodsThe study included a total of 35,465 breast cancer patients who were diagnosed with T1–2 tumours (⩽5.0 cm), negative axillary lymph node status and no distant metastases upon clinical examination between 1st January 1998 and 31st December 2003 in six Comprehensive Cancer Centre regions in the Netherlands. Information on axillary surgery was classified as SNB alone, SNB+axillary lymph node dissection (ALND), ALND alone or none. Patterns of use of axillary surgery were summarised as the proportion of patients receiving each surgery type.ResultsOverall, 25.7% of patients underwent SNB alone, 19.1% underwent SNB+ALND, 50.0% had ALND alone and 5.2% did not have axillary surgery. SNB was more common in women who had breast-conserving surgery: 50.5% of patients who received breast-conserving surgery underwent SNB compared to 40.7% of patients who had mastectomy (p < 0.0001). Amongst patients receiving breast-conserving treatment, 31.7% had SNB as final axillary surgery, whilst 20.5% of patients who had mastectomy had SNB alone (p < 0.0001). The proportion of women who underwent a SNB alone or in combination with ALND increased over the period 1998–2003, from 2.1% to 45.8% and from 6.7% to 24.8%, respectively. There were marked differences in the patterns of dissemination of the use of SNB between regions: by 2003, the difference between the regions with the highest and lowest proportion of use was 25%.ConclusionsSNB has become the standard-of-care for the treatment of breast cancer patients clinically diagnosed with T1–2 tumours, clinically negative lymph nodes and without distant metastases. In 2003, 70.6% of patients with early breast cancer in the Netherlands received SNB, and within this group, 64.9% of patients had SNB as the final axillary treatment. Implementation of SNB may depend on factors associated with regional organisation of care.     

Intermittent versus continuous first-line treatment for HER2-negative metastatic breast cancer: the Stop &; Go study of the Dutch Breast Cancer Research Group (BOOG)

Purpose

For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy.

Methods

In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses.

Results

In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47–0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38–0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13–1.06), although this additional analysis was underpowered for definite conclusions.

Conclusions

This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

     

CD44 enhances tumor aggressiveness by promoting tumor cell plasticity

Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM⁺) and non-aggressive (VM⁻) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic acid. CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation. From these results and the observation that CD44 expression is associated with vasculogenic structures and blood lakes in human Ewing sarcoma tissues, we conclude that CD44 increases aggressiveness in tumors through the process of vasculogenic mimicry.