In August 2017, cyclin‐dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy have been reimbursed in the Netherlands for patients with hormone receptor positive (HR+), HER2 ...negative (HER2−) advanced breast cancer (ABC). This study evaluates the implementation of CDK4/6 inhibitors and changes in treatment choices in the Netherlands. All patients diagnosed with HR+/HER2− ABC in 2009 to 2018 in seven hospitals were selected from the Southeast Netherlands Advanced Breast cancer (SONABRE) registry. The 2‐year cumulative use of CDK4/6 inhibitors since reimbursement date (August 2017) was assessed using competing‐risk methodology in two cohorts. The first cohort included patients with ABC diagnosis between August 2017 and December 2018. The second cohort included patients with ABC diagnosis between 2009 and August 2017, and still alive on August 1, 2017. In addition, treatment choices in the first three lines of therapy in calendar years 2009 to 2018 were evaluated for the total study population. Among patients diagnosed since August 2017 (n = 214), 50% (95% confidence interval CI = 43‐57) received CDK4/6 inhibitors within 2 years beyond diagnosis. Of eligible patients diagnosed before August 2017 (n = 417), 31% (95% CI = 27‐36) received CDK4/6 inhibitors within 2 years following reimbursement. Another 20% of both cohorts are still CDK4/6 inhibitor naïve and on first‐line therapy. The use of chemotherapy decreased in first two lines of therapy between 2009 and 2018 (first‐line: 29%‐13%; second‐line: 26%‐19%). The implementation rate of CDK4/6 inhibitors since reimbursement is currently 50% within 2 years beyond diagnosis and is expected to increase further. The implementation of targeted therapy decreased the use of chemotherapy as first‐line therapy.
What's new?
In the Netherlands, inhibitors of cyclin‐dependent kinase 4/6 (CDK 4/6) are eligible for reimbursement by health insurers. The present report describes implementation patterns of CDK4/6 inhibitors for the treatment of advanced breast cancer since 2017, based on data and observations collected from seven hospitals across the Southeast Netherlands. Analyses show that about half of patients with HR+/HER2‐ metastatic breast cancer are treated with CDK4/6 inhibitors. Following the implementation of these therapies, use of first‐line chemotherapy decreased significantly. Reduced chemotherapy use may have beneficial effects on quality of life for patients, adding value to overall gains in survival.
Moving Breast Cancer Therapy up a Notch Mollen, Erik W J; Ient, Jonathan; Tjan-Heijnen, Vivianne C G ...
Frontiers in oncology,
11/2018, Letnik:
8
Journal Article
Recenzirano
Odprti dostop
Breast cancer is the second most common malignancy, worldwide. Treatment decisions are based on tumor stage, histological subtype, and receptor expression and include combinations of surgery, ...radiotherapy, and systemic treatment. These, together with earlier diagnosis, have resulted in increased survival. However, initial treatment efficacy cannot be guaranteed upfront, and these treatments may come with (long-term) serious adverse effects, negatively affecting a patient's quality of life. Gene expression-based tests can accurately estimate the risk of recurrence in early stage breast cancers. Disease recurrence correlates with treatment resistance, creating a major need to resensitize tumors to treatment. Notch signaling is frequently deregulated in cancer and is involved in treatment resistance. Preclinical research has already identified many combinatory therapeutic options where Notch involvement enhances the effectiveness of radiotherapy, chemotherapy or targeted therapies for breast cancer. However, the benefit of targeting Notch has remained clinically inconclusive. In this review, we summarize the current knowledge on targeting the Notch pathway to enhance current treatments for breast cancer and to combat treatment resistance. Furthermore, we propose mechanisms to further exploit Notch-based therapeutics in the treatment of breast cancer.
Purpose
To spare DCIS patients from overtreatment, treatment de-escalated over the years. This study evaluates the influence of these developments on the patterns of care in the treatment of DCIS ...with particular interest in the use of breast conserving surgery (BCS), radiotherapy following BCS and the use and type of axillary staging.
Methods
In this large population-based cohort study all women, aged 50–74 years diagnosed with DCIS from January 1989 until January 2019, were analyzed per two-year cohort.
Results
A total of 30,417 women were diagnosed with DCIS. The proportion of patients undergoing BCS increased from 47.7% in 1995–1996 to 72.7% in 2017–2018 (
p
< 0.001). Adjuvant radiotherapy following BCS increased from 28.9% (1995–1996) to 89.6% (2011–2012) and subsequently decreased to 74.9% (2017–2018;
p
< 0.001). Since its introduction, the use of sentinel lymph node biopsy (SLNB) increased to 63.1% in 2013–2014 and subsequently decreased to 52.8% in 2017–2018 (
p
< 0.001). Axillary surgery is already omitted in 55.8% of the patients undergoing BCS nowadays. The five-year invasive relapse-free survival (iRFS) for BCS with adjuvant radiotherapy in the period 1989–2010, was 98.7% CI 98.4% – 99.0%, compared to 95.0% CI 94.1% –95.8% for BCS only (
p
< 0.001). In 2011–2018, this was 99.3% CI 99.1% – 99.5% and 98.8% CI 98.2% – 99.4% respectively (
p
= 0.01).
Conclusions
This study shows a shift toward less extensive treatment. DCIS is increasingly treated with BCS and less often followed by additional radiotherapy. The absence of radiotherapy still results in excellent iRFS. Axillary surgery is increasingly omitted in DCIS patients.
No studies are available in which changes over time in characteristics and prognosis of patients with interval breast cancers (ICs) and screen-detected breast cancers (SDCs) have been compared. The ...aim was to study these trends between 1995 and 2018.
All women with invasive SDCs (N = 4290) and ICs (N = 1352), diagnosed in a southern mammography screening region in the Netherlands, were included and followed until date of death or 31 December 2022.
The 5-year overall survival rate of women with SDCs increased from 91.4% for those diagnosed in 1995-1999 to 95.0% for those diagnosed in 2013-2018 (P < 0.001), and from 74.8 to 91.6% (P < 0.001) in the same periods for those with ICs. A similar trend was observed for the 10-year survival rates. After adjustment for changes in tumour characteristics, the hazard ratio (HR) for overall survival was 0.47 (95% confidence interval (CI): 0.38-0.59) for women with SDCs diagnosed in the period 2013-2018, compared to the women diagnosed in the period 1995-1999. For the women with ICs this HR was 0.27 (95% CI: 0.19-0.40).
The prognosis of women with ICs has improved rapidly since 1995 and is now almost similar to that of women with SDCs.
Mutations in the estrogen receptor gene (ESR1), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic ...breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression of ESR1 target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression of ESR1 and its target genes. Samples in this cluster were significantly enriched for mutations in ESR1 and amplifications in FGFR1 and TSPYL. Patients in the other cluster showed relatively lower expression levels of ESR1 and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, including NF1, and ESR1 transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression of ESR1 and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data.
Between January 1, 2011, and December 31, 2016, we studied the incidence, management and outcome of high‐risk breast lesions in a consecutive series of 376,519 screens of women who received biennial ...screening mammography. During the 6‐year period covered by the study, the proportion of women who underwent core needle biopsy (CNB) after recall remained fairly stable, ranging from 39.2% to 48.1% (mean: 44.2%, 5,212/11,783), whereas the proportion of high‐risk lesions at CNB (i.e., flat epithelial atypia, atypical ductal hyperplasia, lobular carcinoma in situ and papillary lesions) gradually increased from 3.2% (25/775) in 2011 to 9.5% (86/901) in 2016 (p < 0.001). The mean proportion of high‐risk lesions at CNB that were subsequently treated with diagnostic surgical excision was 51.4% (169/329) and varied between 41.0% and 64.3% through the years, but the excision rate for high‐risk lesions per 1,000 screens and per 100 recalls increased from 0.25 (2011) to 0.70 (2016; p < 0.001) and from 0.81 (2011) to 2.50 (2016; p < 0.001), respectively. The proportion of all diagnostic surgical excisions showing in situ or invasive breast cancer was 29.0% (49/169) and varied from 22.2% (8/36) in 2014 to 38.5% (5/13) in 2011. In conclusion, the proportion of high‐risk lesions at CNB tripled in a 6‐year period, with a concomitant increased excision rate for these lesions. As the proportion of surgical excisions showing in situ or invasive breast cancer did not increase, a rising number of screened women underwent invasive surgical excision with benign outcome.
What's new?
Screening mammography aims to catch breast cancer early to reduce associated morbidity and mortality. Women with suspect findings at mammography frequently are recalled for further testing with core needle biopsy (CNB). In this investigation, the proportion of high‐risk lesions detected at CNB was found to have tripled among women in the Netherlands who underwent mammographic screening between 2011 and 2016. This increase was accompanied by an increase in lesion excision rates. Of excised lesions, little more than 14% proved to be malignant at two‐year follow‐up. The remainder of lesions exhibited benign pathology, suggesting that many women underwent potentially unnecessary surgery.
Background
Differences in estrogen (ER) and progesterone (PR) expression between invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) could be an underlying reason for the difference ...in chemo-sensitivity and response to hormonal therapy between ILC and IDC. The aim of this study was to investigate the differences in ER and PR expression levels between postmenopausal patients with hormonal receptor-positive ILC and IDC.
Methods
We included all ER and/or PR receptor-positive ILC and IDC, diagnosed between January 2011 and December 2013 from the population-based Netherlands Cancer Registry. A semi-quantitative classification was used to analyze differences in ER/PR expression, which consisted of three ER expression classes: 10–69, 70–89, and ≥90%. Differences in ER and PR expression levels between IDC and ILC were analyzed according to age group, tumor size, axillary nodal status, grade, and HER2 status.
Results
In total, 26,339 ER and/or PR-positive breast cancers were included in the study, of which 17% were ILC and 83% IDC. In patients with IDC, 86% of the tumors showed an ER expression level of 90% or more, compared to 84% in those with ILC. In both IDC and ILC a PR expression level of 90% or more was observed in 54% of the tumors. In postmenopausal patients aged 50–69 years no significant differences could be observed in ER and PR expression levels between ILC and IDC.
Conclusion
Patients with ER and PR-positive ILC and IDC have similar quantitative ER and PR expression profiles, implicating that ER/PR expression is unlikely to be a confounding factor in studies concerning chemo-sensitivity of ILC and IDC.
Objectives
For patients with ductal carcinoma in situ (DCIS), data about the impact of breast MRI at primary diagnosis on the incidence and characteristics of contralateral breast cancers are scarce.
...Methods
We selected all 8486 women diagnosed with primary DCIS in the Netherlands in 2011–2015 from the Netherlands Cancer Registry. The synchronous and metachronous detection of contralateral DCIS (cDCIS) and contralateral invasive breast cancer (cIBC) was assessed for patients who received an MRI upon diagnosis (MRI group) and for an age-matched control group without MRI.
Results
Nineteen percent of patients received an MRI, of which 0.8% was diagnosed with synchronous cDCIS and 1.3% with synchronous cIBC not found by mammography. The 5-year cumulative incidence of synchronous plus metachronous cDCIS was higher for the MRI versus age-matched control group (2.0% versus 0.9%,
p
= 0.02) and similar for cIBC (3.5% versus 2.3%,
p
= 0.17). The increased incidence of cDCIS was observed in patients aged < 50 years (sHR = 4.22, 95% CI: 1.19–14.99), but not in patients aged 50–74 years (sHR = 0.89, 95% CI: 0.41–1.93).
Conclusions
MRI at primary DCIS diagnosis detected additional synchronous cDCIS and cIBC, and was associated with a higher rate of metachronous cDCIS without decreasing the rate of metachronous cIBC. This finding was most evident in younger patients.
Key Points
• Magnetic resonance imaging at primary diagnosis of ductal carcinoma in situ detected an additional synchronous breast lesion in 2.1% of patients.
• In patients aged younger than 50 years, the use of pre-operative MRI was associated with a fourfold increase in the incidence of a second contralateral DCIS without decreasing the incidence of metachronous invasive breast cancers up to 5 years after diagnosis.
• In patients aged over 50 years, the use of pre-operative MRI did not result in a difference in the incidence of a second contralateral DCIS or metachronous invasive breast cancer.
Background
The Z0011 trial initiated a paradigm shift in the axillary treatment of breast cancer patients with a positive sentinel lymph node biopsy (SLNB), disregarding patients with a positive ...ultrasound-guided lymph node biopsy (UGLNB). We examined whether relevant differences exist between these patients to determine if the conclusions of the ACOSOG Z0011 trial are applicable to UGLNB-positive patients.
Methods
Patients diagnosed with invasive breast cancer in the Netherlands between January 2008 and December 2014 were selected from the Netherlands Cancer Registry.
Results
A total of 11,820 cases were included: 9149 cases in the SLNB group and 2671 in the UGLNB group. Multivariate analyses showed that UGLNB-positive patients were older (
p
< 0.001), more likely to have a poorly differentiated tumor (
p
< 0.001), had a negative hormone receptor status (
p
< 0.001), and more often had extensive nodal involvement (
p
< 0.001). However, they were less likely to undergo adjuvant radiation (
p
= 0.004) or systemic therapy (
p
< 0.001). Even after adjusting for these factors, UGLNB-positive patients had a worse overall survival (HR = 1.38; 95% CI 1.23–1.56) than SLNB-positive patients.
Conclusion
This nationwide retrospective study shows that young patients found positive by UGLNB have less favorable disease characteristics and a worse prognosis compared to patients with a positive SLNB. Selection by ultrasound plays an important role when axillary treatment strategies are considered. Hence, the conclusions of the Z0011 trial cannot unconditionally be applied to patients with a positive UGLNB.
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