Introduction
Improvement in overall survival (OS) by locoregional treatment (LRT) of the primary tumor in de novo metastatic breast cancer (MBC) patients remains controversial.
Objective
The aim of ...our study was to evaluate the impact of LRT on OS in a large retrospective cohort of de novo MBC patients, with regard to immunohistochemical characteristics and pattern of metastatic dissemination.
Methods
We conducted a multicentric retrospective study of patients diagnosed with de novo MBC selected from the French Epidemiological Strategy and Medical Economics MBC database (NCT03275311) between 2008 and 2014. Overall, 4276 women were included in the study. LRT comprised either radiotherapy, surgery, or both.
Results
LRT was used in 40% of patients. Compared with no LRT, patients who received LRT were younger (
p
< 0.0001) and were more likely to have only one metastatic site (
p
< 0.0001) or bone-only metastases (
p
< 0.0001). LRT was associated with a significantly better OS based on landmark multivariate analysis at 1-year (hazard ratio 0.65, 95% confidence interval 0.55–0.76,
p
< 0.001). Similar results were observed in all sensitivity analyses, including propensity score matching. In subgroup analysis, LRT was associated with better OS in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (61.6 vs. 45.9 months,
p
< 0.001) and HER2-positive tumors (77.2 vs. 52.6 months,
p
= 0.008), but not in triple-negative tumors (19 vs. 18.6 months,
p
= 0.54), and was also associated with a reduction in the risk of death in visceral metastatic patients (
p
< 0.001).
Conclusions
LRT was associated with a significantly better OS in de novo MBC patients, including patients with visceral involvement at diagnosis; however, LRT did not impact OS in triple-negative MBC.
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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
Abstract
With the approval of new therapies targeting the PI3K pathway, the detection of PIK3CA mutations has become a key factor in treatment management for HR+/HER2− metastatic breast cancer (MBC). ...We developed multiplex digital PCR (dPCR) assays to detect and quantify PIK3CA mutations. A first screening assay allows the detection of 21 mutations, with a drop-off system targeting the 542–546 hotspot mutations combined with the simultaneous detection of N345K, C420R, H1047L and H1047R mutations. In the case of a positive result, a sequential strategy based on other assays that we have developped allows for precise mutation identification. Clinical validity was determined by analyzing plasma circulating free DNA (cfDNA) from 213 HR+/HER2− MBC samples, as well as DNA extracted from 97 available matched tumors from 89 patients. Our assays have shown reliable specificity, accuracy and reproducibility, with limits of blank of three and four droplets for the screening assay. Sixty-eight patients (32%) had at least one PIK3CA mutation detectable in their plasma, and we obtained 83.1% agreement between the cfDNA analysis and the corresponding tumors. The high sensitivity and robustness of these new dPCR assays make them well-suited for rapid and cost-effective detection of PIK3CA mutations in the plasma of MBC patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Background Cabazitaxel, abiraterone acetate (AA), and enzalutamide have been approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) following ...docetaxel chemotherapy. Whether taxanes and next-generation androgen receptor (AR) axis inhibitors are cross-resistant or not is a subject of debate. Objective To evaluate the antitumour activity of cabazitaxel in mCRPC pretreated with abiraterone or enzalutamide. Design, setting, and participants The antitumour activity of cabazitaxel was assessed in patients with mCRPC and progressive disease after treatment with docetaxel and AA. In parallel, cabazitaxel antitumour activity was studied in enzalutamide-resistant models. Outcome measurements and statistical analysis Changes in prostate-specific antigen (PSA) levels and progression-free survival were used to determine the activity of cabazitaxel treatment. Cell proliferation, immunofluorescence, and AR transactivation assay were used in enzalutamide-resistant models. Results and limitations A total of 79 patients who had progressive mCRPC after docetaxel (median: 8 cycles; range: 4–12 mo), and AA (median: 4.8 mo; range:1–55 mo) received cabazitaxel 25 mg/m2 every 3 weeks (median: 6 cycles; range:1–15 cycles). A PSA decline ≥30% was achieved in 48 patients (62%; 95% confidence interval CI, 51–73), and a decline ≥50% was achieved in 28 patients (35%; 95% CI, 25–47). The median progression-free survival and overall survival were 4.4 and 10.9 mo, respectively. In vitro, cabazitaxel decreased cell viability in both enzalutamide-sensitive and enzalutamide-resistant prostate cancer cells within the same range of concentrations. PC3, an AR-negative cell line, exhibited similar sensitivity to cabazitaxel. Conclusions Cabazitaxel and AR-pathway inhibitors are not cross-resistant. Preclinical data suggest that cabazitaxel activity does not act mainly through AR axis inhibition. Patient summary The antitumour activity of cabazitaxel, a chemotherapy agent, was studied in prostate cancer resistant to conventional hormonal therapy and to more recent endocrine therapies (abiraterone or enzalutamide). Cabazitaxel retained anticancer activity in more than half of the cases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The outcomes and best treatment strategies for germline BRCA1/2 mutation (gBRCAm) carriers with metastatic breast cancer (MBC) remain uncertain. We compared the overall survival and the first line ...progression free survival (PFS1) of patients with a gBRCAm identified at initiation of first‐line treatment with those of BRCA wild‐type (WT) and not‐tested (NT) individuals in the ESME real‐world database of MBC patients between 2008 and 2016 (NCT03275311). Among the 20 624 eligible patients, 325 had a gBRCAm, 1138 were WT and 19 161 NT. Compared with WT, gBRCAm carriers were younger, and had more aggressive diseases. At a median follow‐up of 50.5 months, median OS was 30.6 (95%CI: 21.9‐34.3), 35.8 (95%CI: 32.2‐37.8) and 39.3 months (95% CI: 38.3‐40.3) in the gBRCAm, WT and NT subgroups, respectively. Median PFS1 was 7.9 (95%CI: 6.6‐9.3), 7.8 (95%CI: 7.3‐8.5) and 9.7 months (95%CI, 9.5‐10.0). In the multivariable analysis conducted in the whole cohort, gBRCAm status had however no independent prognostic impact on OS and PFS1. Though, in the triple‐negative subgroup, gBRCAm patients had better OS and PFS1 (HR vs WT = 0.76; 95%CI: 0.60‐0.97; P = .027 and 0.69; 95% CI: 0.55‐0.86; P = .001, respectively). In contrast, in patients with HR+/HER2 negative cancers, PFS1 appeared significantly and OS non significantly lower for gBRCAm carriers (PFS1: HR vs WT = 1.23; 95%CI: 1.03‐1.46; P = .024; OS:HR = 1.22, 95% CI: 0.97‐1.52, P = .089). In conclusion, gBRCA1/2 status appears to have divergent survival effects in MBC according to IHC subtype.
What's new?
Despite the recent approval of novel therapeutics for germline BRCA1/2‐mutated metastatic breast cancer, data regarding outcomes and optimal treatment strategies are lacking. This study assessed the impact of germline BRCA mutations on metastatic breast cancer survival using data from a cohort of patients treated in an era predating PARP inhibitors. Although germline BRCA mutation had no independent prognostic impact on survival, divergent prognostic effects according to tumor subtype were observed. These effects were pronounced among germline mutation carriers with luminal breast cancer, who experienced worse progression‐free survival. The observations highlight the importance of deciphering BRCA status early in clinical care.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Most women diagnosed with malignant ovarian germ cell tumors have curable disease and experience excellent survival with manageable treatment-associated morbidity, related both to tumor biology and ...improvements in treatment over the last 4 decades. Malignant ovarian germ cell tumors occur predominantly in girls, adolescents, and young women and are often unilateral tumors of early stage, although advanced-stage disease occurs in approximately 30% of patients. Tumors are usually chemosensitive, thereby allowing fertility-sparing surgery in most women with high chance of cure. Differences in practice do exist among providers in various subspecialties and geographic areas. In most settings, collaborative efforts among specialties allow the optimal treatment of women with these rare tumors, and implementation of standard guidelines at an international level should translate to effective clinical trial design, rapid accrual to clinical trials, and universally improved patient outcomes. This consensus guideline represents a summary of recommendations for diagnosis and management that has been agreed upon by cooperative groups worldwide. It builds upon individual publications including previously published summary documents and provides the most current practice standards validated worldwide.
Highlights • Chemotherapy and radiotherapy have direct toxic effects on spermatogonia. This effect is dose-related and drug-specific. • In male cancer survivors, infertility and persistent a ...zoospermiais a more common long-term adverse effect than hypogonadism because germ cells are more sensitive to chemotherapy and radiotherapy than leydig cells. • Testicular cancer is often associated with infertility not related to cytotoxic treatment. • The mechanisms of cytotoxic agent and radiation treatment gonadal toxicity in women include the impairment of follicular maturation by arresting rapidly dividing cells or direct toxicity on quiescent primordial follicles or the combination of two. • The extent of damage depends on the type of the drug, cumulative doses, age and pre-treatment gonadal status of the patients. • Gonadal toxicity and compromise of reproductive function are more efficiently prevented and treated if addressed before treatment initiation. • The most effective and established means of preserving fertility in young survivors from cancer are oocyte and embryo cryopreservation in women and sperm cryopreservation in men before the initiation of therapy. • Alternative and promising methods include cryopreservation of unfertilized oocytes, ovarian tissue laparoscopic excision with subsequent grafting and freezing before treatment and harvesting of immature oocytes and in vitro maturation. • The role gonadotropin analogues (GnRH) administered during the course of chemotherapy in the preservation of female fertility should be reconsidered.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
PARP inhibitors (PARPi) have revolutionized the management of high-grade epithelial ovarian cancer (HGOC) treatment. However, a significant number of patients relapse or progress under PARPi, leading ...to the introduction of a new line of systemic therapy such as chemotherapy. In patients with a limited number of metastatic sites at progression, −referred to as an oligometastatic progression- a potential indication for local therapy followed by re-introduction or continuation of PARPi treatment rather than initiating a new line of chemotherapy could be proposed. However, the impact of such strategies on progression free survival (PFS) in these patients remains unknown.
This international multicenter retrospective study evaluated the efficacy of PARPi continuation or re-introduction in patients with HGOC after local treatment for oligometastatic progression. The main objective was to assess PFS under PARPi after local therapy (PFS post-LT). Secondary objectives included safety and overall survival (OS).
74 patients were identified in 20 centers between April 2020 and November 2021. 65% of patients were BRCA mutated and 92% had received ≥2 lines of prior systemic chemotherapy before the initial introduction of PARPi. Main progression sites were lymph nodes (42%), peritoneum (27%), liver (16%), other visceral (16%) and abdominal wall (4%). Local therapies included radiotherapy (45%), surgery (43%), both (7%), percutaneous thermal ablation (4%) or chemoembolization (1%). Median PFS post-LT was 11.5 months 95% CI 7.4; 17.2. After a median follow up of 14.8 months, 6 patients (8.1%) discontinued PARPi due to toxicity. The 1-year overall survival rate was 90.7% 95% CI 79.1; 96.0.
With close to one year without progression or introduction of a new line of systemic therapy, this study reports the feasibility and potential benefit of this original strategy in patients with oligometastatic progression under PARPi.
•Oligoprogression on PARP inhibitors is a potential indication for local therapy followed by reintroduction or continuation of PARP inhibitors.•This is a multicenter international retrospective cohort-type study.•The sites of progression were mainly lymph nodes and the local treatment mainly radiotherapy.•After a median follow-up of 14.8 months, median progression-free survival after local treatment was 11.5 months.•Patients with a single target lesion seem to benefit the most from this strategy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a ...central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.
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► PDXK is required for optimal cisplatin responses in cancer cells ► PN, PDXK’s substrate, aggravates CDDP cytotoxicity in vitro and in vivo ► Vitamin B6 metabolism affects cellular responses to multiple stress conditions ► PDXK expression levels influence disease progression in NSCLC patients
Kroemer and colleagues have discovered that vitamin B6 metabolism not only influences the response of cancer cells to the antineoplastic agent cisplatin, in vitro and in vivo, but also plays a critical role in the cellular management of multiple stress conditions. Accordingly, high expression levels of PDXK, the enzyme that generates the bioactive form of vitamin B6, constitute a good prognostic biomarker in patients with NSCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
To assess awareness of bladder cancer (BCa) in France.
Methods
The French nationwide observational survey EDIFICE 6 was conducted online (26 June–28 July 2017) in 12,046 individuals (age, ...18–69 years). The present analysis focuses on laypersons’ knowledge of the severity and frequency of BCa, signs and symptoms, associated risk factors and screening tests. Quantitative data were expressed as means and standard deviation, and categorical data as percentages.
Results
Analyses were conducted on 11,313 questionnaires. Among the top five acknowledged risk factors for BCa, tobacco was ranked as having the second lowest impact (5.9/10 2.5). Only 28% of the study population were aware that active tobacco smoking is a major risk factor for BCa (rating ≥8/10); 61% of the study population was unaware of the existence of any signs or symptoms of BCa, and 69% was not able to cite any of the most widely used diagnostic tests.
Conclusions
We found that the French population has a poor knowledge of BCa risk factors, early signs and diagnostic tests. Effective prevention of BCa requires dissemination of clear information and prevention messages to the lay population, focusing particularly on tobacco consumption and early signs of the disease.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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