Efficacy of endocrine therapy in HR+/HER2- metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation.
The ESME metastatic breast cancer platform (NCT03275311) is a ...French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1).
A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR 95% CI 1.26 1.03-1.55). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR 95% CI = 1.54 1.03-2.32) and PFS1 (adjusted HR 95% CI 1.58 1.17-2.12) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 0.88-1.41, p = 0.350; PFS1: 1.09 0.90-1.31, p = 0.379).
In this large cohort of HR+/HER2- MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.
Everolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory ...study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial.
Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells).
A total of 55 primary tumor samples from the TAMRAD trial—25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group—were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6–34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient.
A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.
Options in second-line therapy after doxorubicin-based chemotherapy for metastatic/advanced leiomyosarcoma include gemcitabine (G), trabectedin and pazopanib (P) monotherapy. Currently, no ...combination therapy is better than monotherapy. LMS03 is an open-label multicentre single-group phase II study designed to assess the efficacy and tolerance of G + P in the second-line setting.
Patients (pts), ECOG ≤2, with metastatic leiomyosarcomas (LMS) after first-line doxorubicin chemotherapy failure were eligible. Pts were treated with G 1000 mg/m2 on days 1 and 8 of each 21 days (maximum eight cycles), in combination with oral daily P (800 mg), until disease progression/toxicity. 9-month progression-free survival (PFS) rate was the primary endpoint. Inacceptable and promising 9-month PFS rates were defined, in the intent-to-treat population, as 32% and 44%.
106 pts were included with a mean age of 59.8 years and an ECOG 0 in 63.5%; the primary tumour site was uterus in 61%. Pts were treated with P + G for a median of 3.8 mo, and P for a median of 4.2 mo. The 9-month PFS rate was 32.1% (95% CI 23.1–41.1). After a median follow-up of 14.2 months, the PFS was 6.5 months (95% CI 5.6–8.2), and the overall survival was 22.4 months (95% CI 16.9–26.5). The best response was 23.8%. The most frequent reported grade 3–4 adverse events were haematological.
LMS03 failed to show that second-line therapy, with gemcitabine combined with pazopanib, followed by pazopanib alone, was beneficial for advanced LMS patients.
Eudract N°2011-001308-36 and NCT01442662.
•Gemcitabine combined with pazopanib in second-line leiomyosarcoma after doxorubicine failure is feasible without limiting toxicity.•The 12-week disease control rate was 83.6%, and the best response during the treatment was 23.8%.•The LMS03 study failed to meet its primary objective but is nearly positive when considering per-protocol results with a median PFS 7.1 months.
Purpose
Older cancer patients are underrepresented in clinical trials. We aimed to evaluate the enrollment of older women aged 70 years old (yo) or over with metastatic breast cancer (MBC) in ...clinical trials.
Methods
We used the national Epidemio-Strategy and Medical Economics MBC Data Platform, a French multi-center real-life database. We selected MBC women over 70yo, without central nervous system metastases, with at least one line of systemic treatment, between January 1st, 2008 and December 31st, 2016, and had no other cancer in the 5 years before MBC. The primary objective was to evaluate the proportion of patients enrolled in clinical trials according to their age. Secondary objective was to identify variables associated with enrollment in older ones.
Results
5552 women were aged ≥ 70 (median 74yo; IQR 72–77). 14,611 were less than 70. Of the older ones, 239 (4%) were enrolled in a clinical trial during first line of treatment, compared with 1529 (10.5%) for younger ones. Multivariable analysis of variables predicting for enrollment during first line of treatment in older patients were younger age (OR 0.50 95%CI 0.33–0.76 for the 80–85yo class; OR 0.17 95%CI 0.06–0.39 for the 85yo and more class), good ECOG Performance Status (PS 0–1) (OR 0.15 95%CI 0.08–0.27 for the PS 2–4 class), HER2 + disease (OR 1.78 95%CI 1.27–2.48), type of treatment (chemotherapy/targeted therapy/immunotherapy OR 5.01 95%CI 3.13–8.18), and period (OR 1.65 95%CI 1.22–2.26 for 2012–2016, compared to 2008–2011).
Conclusion
In this large database, few older MBC patients were enrolled in a trial compared with younger ones.
In a comparison of tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin inhibitor (mTORi) in patients with metastatic clear-cell renal cell carcinoma who received a 1st-line TKI for at ...least 6 months, the TKI-TKI sequence was favored over the TKI-mTORi. Long-term 2nd-line responders were more likely to have received a second TKI and to have been long-term responders to a 1st-line TKI.
Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1).
Retrospective multicenter study (2004–2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). End points: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM).
Sequence effect in the overall cohort was in favor of the TKI–TKI sequence over the TKI–mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI–TKI superiority was attributed in large part to the 11–22 month (TD1) subgroup of patients which displayed significantly better outcomes HR ≈ 0.5; median PFS (months): 9.4 (5.9–12.2) versus 3.9 (3.0–5.5), P = 0.003; TTF(months): 8.0 (5.5–11.0) versus 3.6 (3.0–4.6), P = 0.009. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI.
m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.
We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory ...breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab.
Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4ml of blood, respectively, with the CellSearch System.
From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P<0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P<0.01, HR 2.80) and shorter 3-year overall survival (OS) (P<0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value.
In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.
Sunitinib is a standard of care for metastatic renal cell carcinoma (mRCC). Hypothyroidism is frequently observed under sunitinib therapy. This study was conducted to prospectively determine the ...correlation between thyroid function and progression-free survival (PFS) in this population.
One hundred and eleven mRCC patients treated with sunitinib were evaluated for serum thyroid-stimulating hormone (TSH) and T4 levels before treatment and every 6 weeks during treatment. Survival was analysed according to a landmark method with a cut-off of 6 months, excluding early progressive or early-censored patients.
Out of the 102 patients with normal baseline thyroid function, 53% developed thyroid dysfunction, including 95% hypothyroidisms out of which 90.9% received L-thyroxine replacement. Median time to TSH alteration was 5.4 months. Median PFS was 11.7 months for the entire population. Median PFS was not different between the groups with abnormal or normal thyroid function after 6 months of treatment (18.9 and 15.9 months, respectively, log-rank P = 0.94, hazard ratio = 1.02, 95% confidence interval = 0.54–1.93). There was no difference even after adjustment for Memorial Sloan-Kettering Cancer Centre classification and therapy line.
Abnormal thyroid function with hormonal substitution did not increase survival in our population, independent of initial prognosis and previous treatments. Larger comparative studies are deserved to validate these conclusions.
The estimated rate of de novo metastatic breast cancer (dnMBC) at the time of diagnosis is between 5 to 12%. International guidelines recommend metastatic work-up (MWU) only in women with advanced ...breast cancer. The purpose of this study was to describe the characteristics and prognosis of patients with dnMBC diagnosed without an initial indication for MWU.
We conducted a retrospective, comparative study in dnMBC patients selected from the ESME-MBC cohort. Patients were treated in France between 2008 and 2016. We compared two populations: patients in whom dnMBC was diagnosed by staging although not indicated by guidelines (non-guideline staging NGS) and those in whom dnMBC was diagnosed by guideline staging (GS).
During the study period, 22,463 patients with MBC were included in the ESME cohort. Among them, 6698 were dnMBC patients. In 247 of these patients (6% of dnMBC and 1% of the overall population), dnMBC was diagnosed by non-guideline staging. Women in this group were significantly younger (57 vs. 59 years, p = 0.02) and had fewer metastatic sites at diagnosis than dnMBC-GS patients. The two groups were not significantly different in terms of the other characteristics. Overall survival (OS) and progression-free survival (PFS) were better in the dnMBC-NGS group than in the dnMBC-GS group. The impact on survival was confirmed by univariate and multivariate analysis (HR 1.83 1.31–2.57, p < 0.01).
This study provides the first description of a very specific population. These patients with dnMBC-NGS were younger and more likely to have oligometastatic disease with a better prognosis.
•T1/T2 N0 de novo metastatic breast cancer (MBC) represented 6% of all de novo MBC.•Metastatic diagnosis in this population implied an unrecommended workup.•These patients were younger with oligometastatic disease and had a better prognosis.•Locoregional therapy prior to diagnosis in this population did not change survival.
Who dies from prostate cancer? Patrikidou, A; Loriot, Y; Eymard, J-C ...
Prostate cancer and prostatic diseases,
12/2014, Letnik:
17, Številka:
4
Journal Article
Recenzirano
Odprti dostop
During the last 30 years, there has been a major shift in initial staging in prostate cancer (CaP) in Western countries, with the incidence of metastases at diagnosis decreasing from over 50% in the ...1970s to currently less than 10%. Yet, CaP is still the second cause of cancer death in men. We used two monthly curated databases of patients with castration-resistant prostate cancer (CRPC) to describe the natural history of patients dying of CaP in the modern era.
The outcome of 190 men with metastatic CRPC treated from 2008 to 2011 was studied. The characteristics of the patients who died from CaP (n = 113 patients, 61%) were analyzed.
All 113 patients who died of CaP were assessable for the presence of metastases at diagnosis. Sixty-three patients (56%) had detectable metastases at diagnosis: 67%, 11% and 43% had bone, visceral and lymph node metastases, respectively. The median time to CRPC was 16 months and median overall survival (OS) was 5.2 years.Among the patients with localized CaP at diagnosis (n = 50, 44%), 46% had T stage ⩾ 3 and 38% had a Gleason score ⩾ 8. Overall, 64% of patients were classified as having a high-risk CaP. Only 26% who died from CaP had a Gleason score ⩽ 6. Median OS was 8.8 years.
In the modern era, approximately half of the patients who die from CaP have metastases at diagnosis. The paradigm of progression from localized disease to metastasis and eventually death is only represented in the other half, although possible initial screening and staging errors ought to be taken into consideration. More efforts are needed to conduct trials in patients with newly diagnosed metastatic CaP.
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