Purpose
A major question when treating HR+/HER2− metastatic breast cancer (MBC) is whether early introduction of chemotherapy (CT) increases endocrine resistance. We aimed to describe ...progression-free survival (PFS) under first endocrine therapy (ET) depending on whether given before or after CT in a large nationwide cohort, in the pre-CDK era.
Methods
The real-life retrospective ESME database includes all patients with MBC whose first-line treatment was initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. Our primary objective was to compare PFS from start of first ET in patients with HR+/HER2− MBC who received ET or CT first.
Results
We identified 6293 patients who received at least one ET line during their first two therapeutic lines for MBC. As first-line therapy, 3832 (60.9%) received ET alone (ET1 1st group), whilst 2461 (39.1%) received CT, including 2024 patients (32.2%) with maintenance ET after CT (ET1 after CT group). Median PFS under first ET was 12.4 months (95% CI 11.9–13.1) in ET 1st group vs. 12.6 months in ET1 after CT group (95% CI 12.1–13.4), HR 0.96 (95% CI 0.90–1.01,
P
= 0.1277).
Conclusions
PFS under first ET appears identical whether prescribed before or after chemotherapy. These data suggest chemotherapy does not promote endocrine resistance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Taxanes are one of the most effective chemotherapies (CT) in breast cancer (BC), but the efficacy of taxanes rechallenge in early metastatic relapse has been poorly studied in patients previously ...treated by taxanes in the (neo)adjuvant setting. Our study aimed to analyse the efficacy of taxane rechallenge in case of early metastatic relapse in a multicentre retrospective observational study compared with other chemotherapies.
We analysed the French national ESME metastatic BC (MBC) database and selected HER2- MBC patients who received CT in first-line treatment for a metastatic relapse occurring 3–24 months after previous (neo)adjuvant taxanes treatment.
Of 23,501 female patients with MBC in ESME, 1057 met the selection criteria. 58.4% received a taxane-based regimen (75.4% concomitant bevacizumab) and 41.6% received other CT.
In hormone-receptor positive (HR+)/HER2- MBC, multivariate analysis showed no difference in OS between taxanes without bevacizumab compared to other CT (HZR = 1.3 0.97; 1.74, but taxanes was significantly associated with worse PFS (HZR = 1.48 1.14; 1.93).
In TNBC, taxanes without bevacizumab and carboplatin/gemcitabine were not superior to other CT for OS (HZR = 1.07 0.79; 1.44 and HZR = 0.81 0.58; 1.13, respectively), while for PFS, taxanes was inferior (HZR = 1.33 1.06–1.67) and carboplatin plus gemcitabine was superior to other CT (HZR = 0.63 0.46; 0.87).
For both subtypes, the worse outcome observed with paclitaxel was no longer observed with the addition of bevacizumab.
With the limitation of retrospective design, taxanes rechallenge in early metastatic relapse of BC may result in a worse PFS in TNBC and HR+/HER2- MBC, which was not observed with the addition of bevacizumab.
•Patients with HER2-advanced breast cancer (ABC) have often previously received taxanes in the (neo)adjuvant setting.•Current guidelines suggest a rechallenge by taxanes in ABC with DFI≥12 months, few data are available for DFI ≤24 months.•Taxane rechallenge in early metastatic relapse of BC (DFI ≤24 months) may result in a worse PFS in TNBC and HR+/HER2- ABC.•In TNBC, the addition of bevacizumab to taxanes improves PFS and OS for DFI ≤24 months.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
High Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in ...patients with metastatic breast cancer (MBC).
The National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers.
Of 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m2 (range 12.1–66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI 46.2–48.5) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02–1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect.
Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor.
•This is the first large multicenter cohort reporting BMI’s effect on outcomes among patients with metastatic breast cancer.•Overweight or obese status does not negatively influence outcome of metastatic breast cancer patients, whatever the subtype.•Underweight is a strong negative independent prognostic factor on outcomes, whatever the subtype.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background:
As a result of progress in diagnosis and treatment, there is a growing prevalence of metastatic breast cancer (MBC) with isolated CNS metastases. This study describes the largest-to-date ...real-life cohort of this clinical setting and compares it to other clinical presentations.
Methods:
We retrospectively analysed the French Epidemiological Strategy and Medical Economics (ESME) MBC database including patients who initiated treatment for MBC between 2008 and 2016. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Descriptive statistics and multivariate Cox model were used.
Results:
Of 22,266 patients, 647 (2.9%) and 929 (4.2%) patients had isolated first-site CNS metastases or combined with extra-CNS metastases, with longer OS for the group with isolated CNS metastases (16.9 versus 13.9 months, adjusted HR = 1.69 (95% CI: 1.50–1.91), p < 0.001). Among the 541 (2.4%) patients with isolated CNS metastases and no intrathecal therapy (excluding leptomeningeal metastases), HER2+ cases were preponderant over TN or HR+ /HER2− cases (41.6% versus 26.1% versus 28.5%, respectively, p < 0.01). The treatment strategy consisted of a combination of local treatment and systemic therapy (49.2%), local treatment only (35.5%) or systemic therapy only (11.4%), or symptomatic therapy only (3.9%). Median PFS was 6.1 months (95% CI: 5.7–6.8). Median OS was 20.7 months (95% CI: 17.3–24.3), reaching 37.9 months (95% CI: 25.9–47.6) in the HR+ /HER2+ subgroup. Older age, TN subtype, MBC-free interval of 6–12 months, lower performance status, and WBRT were associated with poorer survival. Patients who received systemic therapy within 3 months from MBC diagnosis had longer OS (24.1 versus 16.1 months, p = 0.031), but this was not significant on multivariate analysis HR = 1.0 (95% CI: 0.7–1.3), p = 0.806.
Conclusions:
Patients with isolated CNS metastases at MBC diagnosis represent a distinct population for which the role of systemic therapy needs to be further investigated in prospective studies.
PTEN plays a well‐established role in the negative regulation of the PI3K pathway, which is frequently activated in several cancer types, including breast cancer. A nuclear function in the ...maintenance of chromosomal stability has been proposed for PTEN but is yet to be clearly defined. In order to improve understanding of the role of PTEN in mammary tumorigenesis in terms of a possible gene dosage effect, its PI3K pathway function and its association with p53, we undertook comprehensive analysis of PTEN status in 135 sporadic invasive ductal carcinomas. Four PTEN status groups were defined; complete loss (19/135, 14%), reduced copy number (19/135, 14%), normal (86/135, 64%) and complex (11/135, 8%). Whereas the PTEN complete loss status was significantly associated with estrogen receptor (ER) negativity (p=0.006) and in particular the basal‐like phenotype (p<0.0001), a reduced PTEN copy number was not associated with hormone receptor status or a particular breast cancer subtype. Overall, PI3K pathway alteration was suggested to be involved in 59% (79/134) of tumors as assessed by human epidermal growth factor receptor 2 overexpression, PIK3CA mutation or a complete loss of PTEN. A complex PTEN status was identified in a tumor subgroup which displayed a specific, complex DNA profile at the PTEN locus with a strikingly similar highly rearranged pan‐genomic profile. All of these tumors had relapsed and were associated with a poorer prognosis in the context of node negative disease (p=1.4 × 10−13) thus may represent a tumor subgroup with a common molecular alteration which could be targeted to improve clinical outcome.
What's new?
PTEN plays a well‐established role in the negative regulation of the PI3K pathway, which is frequently activated in breast cancer, and may also help maintain chromosomal stability. Here the authors analyzed PTEN status to improve understanding of the role of PTEN regarding a possible gene dosage effect, its PI3K pathway function, and its association with p53. Breast carcinomas were classified into 4 PTEN status groups, one of which displayed a specific, complex DNA profile and corresponded to tumors that had relapsed and presented a poorer prognosis. Furthermore, for most tumors, loss of p53 was not required to escape PTEN‐induced senescence.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Randomized controlled trials (RCTs) represent the best evidence in oncology practice. The aim of this study was to assess the reporting quality of sarcoma RCTs and to identify significant predictors ...of quality.
Two investigators searched MEDLINE for pediatric and adult bone and soft tissue sarcoma RCTs published between January 1988 and December 2008. The quality of each report was assessed by using a 15-point overall reporting quality score based on 15 items from the revised Consolidated Standards of Reporting Trials (CONSORT) statement (overall quality score OQS range, 0 to 15 points). Concealment of allocation, appropriate blinding, and analysis according to intention-to-treat principle were assessed separately because of their crucial methodologic importance by using a 3-point key methodologic index score (MIS; range, 0 to 3).
We retrieved 72 relevant RCTs that included 16,029 patients. The median OQS was 9.5. Allocation concealment, blinding, and analysis by intent to treat were reported only in 21 (29%), nine (12.5%), and 23 (32%) of the 72 RCTs, respectively. The median MIS was 1 with a minimum of 0 and a maximum of 2. On multivariate analysis, publication after 1996 and high impact factor remained independent and significant predictors of improved OQS. The sole variable associated with improved MIS was the publication of chemotherapy-only trials.
Although the overall quality of sarcoma RCTs reporting has improved over time, reporting of key methodologic issues remains poor. This may lead to biased interpretation of sarcoma trial results.
Background
Proof of concept studies has reported that circulating endothelial cell (CEC) count may be associated with the outcome of HER2-negative metastatic breast cancer (mBC) patients treated by ...chemotherapy and the anti-VEGF antibody bevacizumab. We report the results obtained in an independent prospective validation cohort (COMET study, NCT01745757).
Methods
The main baseline criteria were HER2-negative mBC, performance status 0–2 and no prior chemotherapy for metastatic disease. CECs were detected by CellSearch® from 4 ml of blood at baseline and after 4 weeks of weekly paclitaxel and bevacizumab therapy. CEC counts (considered both as a continuous variable and using the previously described 20 CEC/4 ml cutoff) were associated with clinical characteristics and progression-free survival (PFS).
Results
CEC count was obtained in 251 patients at baseline and in 207 patients at 4 weeks. Median baseline CEC count was 22 CEC/4 ml (range 0–2231). Baseline CEC counts were associated with performance status (
p
= 0.02). No statistically significant change in CEC counts was observed between baseline and 4 weeks of therapy. High baseline CEC count was associated with shorter PFS in univariate and multivariate analyses (continuous:
p
< 0.001; dichotomized: HR 1.52, 95% CI 1.15–2.02,
p
= 0.004). CEC counts at 4 weeks had no prognostic impact.
Conclusion
This study confirms that CEC count may be associated with the outcome of mBC patients treated with chemotherapy and bevacizumab. However, discrepancies with previous reports in terms of both the timing of CEC count and the direction of the prognostic impact warrant further clinical investigation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, ...anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta‐analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first‐line anthracycline‐based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first‐line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first‐line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First‐line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long‐term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first‐line treatment of patients with human epidermal growth factor receptor 2–negative MBC.
The available evidence for the use of capecitabine as a single agent in the first‐line treatment of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer is reviewed.
Abstract
Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are two cancer-derived blood biomarkers that inform on patient prognosis and treatment efficacy in breast cancer. We ...prospectively evaluated the clinical validity of quantifying both CTCs (CellSearch) and ctDNA (targeted next-generation sequencing). Their combined value as prognostic and early monitoring markers was assessed in 198 HER2-negative metastatic breast cancer patients. All patients were included in the prospective multicenter UCBG study COMET (NCT01745757) and treated by first-line chemotherapy with weekly paclitaxel and bevacizumab. Blood samples were obtained at baseline and before the second cycle of chemotherapy. At baseline, CTCs and ctDNA were respectively detected in 72 and 74% of patients and were moderately correlated (Kendall’s
τ
= 0.3). Only 26 (13%) patients had neither detectable ctDNA nor CTCs. Variants were most frequently observed in
TP53
and
PIK3CA
genes
. KMT2C
/
MLL3
variants detected in ctDNA were significantly associated with a lower CTC count, while the opposite trend was seen with
GATA3
alterations. Both CTC and ctDNA levels at baseline and after four weeks of treatment were correlated with survival. For progression-free and overall survival, the best multivariate prognostic model included tumor subtype (triple negative vs other), grade (grade 3 vs other), ctDNA variant allele frequency (VAF) at baseline (per 10% increase), and CTC count at four weeks (≥5CTC/7.5 mL). Overall, this study demonstrates that CTCs and ctDNA have nonoverlapping detection profiles and complementary prognostic values in metastatic breast cancer patients. A comprehensive liquid-biopsy approach may involve simultaneous detection of ctDNA and CTCs.
Trastuzumab-emtansine (T-DM1), as well as lapatinib plus capecitabine were proven effective in two Phase III studies, following first-line trastuzumab plus a taxane. The introduction of dual HER2 ...blockade by trastuzumab and pertuzumab as first-line has positioned T-DM1 into second-line, and lapatinib plus capecitabine beyond, without formal evaluation of these strategies.
ESME Data Platform (NCT03275311) included individual data from all patients aged ≥18 years, in whom first-line treatment for metastatic breast cancer (MBC) was initiated between January 1, 2008 and December 31, 2016 in one of the 18 French Comprehensive Cancer Centers. The efficacy of T-DM1 and lapatinib plus capecitabine combination, following double blockade associating trastuzumab and pertuzumab were evaluated in this national real-life database. Eligibility criteria were: female, MBC, HER2+ tumor, first-line taxane-based chemotherapy and dual HER2-blockage by trastuzumab plus pertuzumab. Cohort A received second-line T-DM1, and Cohort B second-line T-DM1 and third or fourth-line lapatinib plus capecitabine.
Cohort A comprised 233 patients, and Cohort B 47 patients. Median progression-free survival (PFS) was 7.1 months in Cohort A and 4.6 months in Cohort B. Median overall survival were 36.7 months and 12.9 months, respectively. PFS was significantly dependent on the preceding treatment line's duration. In cohort A, HER2 expression status was a significant predictive factor of PFS.
First-line trastuzumab plus pertuzumab do not markedly diminish T-DM1's efficacy in second-line. Similarly, sequential treatment with trastuzumab plus pertuzumab then T-DM1 does not noticeably modify the efficacy of lapatinib plus capecitabine.
•French real-life cohort.•Dual blockade HER2 does not markedly diminish T-DM1's activity in second-line and lapatinib's activity in third or fourth line.•The second-line (T-DM1) PFS was significantly longer when the first-line treatment with trastuzumab plus pertuzumab was ≥12 months.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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