Adjuvant chemotherapy with new cytotoxic agents for breast cancer must be properly assessed for toxicity.
To describe adverse events associated with adjuvant chemotherapy for breast cancer, which led ...to premature termination of a clinical trial.
We conducted a prospective randomized multicenter study (Reposant sur des Arguments Pronostiques et Predictifs RAPP-01) to compare the effectiveness of 2 chemotherapy regimens. Patients (women aged 18-70 years) had primary unilateral breast cancer and either a moderate number of positive axillary lymph nodes (< or =3) or no positive axillary lymph nodes (N0), but were at a high risk of relapse. Patients were treated at 11 French cancer referral centers from June 1999 through January 2003. Primary prophylaxis for febrile neutropenia was not recommended in the study protocol.
Doxorubicin, 50 mg/m2, plus docetaxel, 75 mg/m2, or doxorubicin, 60 mg/m2, plus cyclophosphamide, 600 mg/m2, given postoperatively for 4 courses.
The main end point was the disease-free survival rate at 5 years, as estimated using the Kaplan-Meier product limit method. Secondary end points included safety, which is the focus of this article, and overall survival.
A total of 627 women were enrolled. Median follow-up is currently too short (24 months) to analyze the primary end point. The trial was terminated prematurely when 2 deaths related to drug toxicity and 1 case of perforative peritonitis occurred among patients with febrile neutropenia, all in the doxorubicin-docetaxel group. The incidence of febrile neutropenia was significantly higher with the doxorubicin-docetaxel regimen (40.8%) than with the doxorubicin-cyclophosphamide regimen (7.1%) (P<.001).
A high risk of life-threatening complications associated with the doxorubicin-docetaxel regimen was found in this open-label controlled trial. The doxorubicin-docetaxel combination should not be considered as an alternative to the doxorubicin-cyclophosphamide regimen outside carefully designed studies that include primary prophylaxis for febrile neutropenia.
Eribulin is approved for advanced breast cancers refractory to anthracyclines and taxanes. Efficacy according to sensitivity to previous therapies has been poorly explored.
Safety data were collected ...prospectively and we retrospectively collected efficacy data from the five French centres that participated in the Eribulin E7389-G000-398 expanded access program. Our main objectiveswere exploration of safety and analysis of eribulin efficacy (progression-free survival PFS and overall survival OS) according to sensitivity to the last microtubule-inhibiting agent administered.
Median eribulin treatment duration was 3.3 months for the 250 patients included in this prospective single-arm study. Two hundreds and thirty-nine patients (95.6%) experienced an adverse event (AE) related to treatment including 129 (51.6%) with grade ≥ 3 AEs. The most frequently observed toxicities were cytopenias (59.6% of included patients), gastrointestinal disorders (59.2%), and asthenia (56.4%). The most frequent grade 3-4 AE was neutropenia (37.2% with 4.8% febrile neutropenia). Median PFS and OS were 4.6 and 11.8 months, respectively. Patients classified as responders to the last microtubule-inhibiting therapy had a longer OS (hazard ratio HR, 0.69; 95% confidence interval CI, 0.51 to 0.94; p=0.017), and tended to display a better PFS (HR, 0.78; 95% CI, 0.58 to 1.04; p=0.086). OS improvement was still significant in multivariate analysis (adjusted HR, 0.53; 95% CI, 0.35 to 0.79; p=0.002).
This work based on a prospective study suggests that identification of patients likely to be more sensitive to eribulin could be based on their previous response to microtubules inhibitors.
Abstract Endocrine therapy is the corner stone treatment for postmenopausal women with hormone receptor-positive metastatic breast cancer (MBC). Besides tamoxifen and many older agents, recently ...developed endocrine agents for the treatment of MBC include the third generation aromatase inhibitors (AI) – anastrozole, exemestane, letrozole – and the pure oestrogen receptor antagonist fulvestrant. As treatment of breast cancer evolves, both tamoxifen and the AIs are being increasingly used in the adjuvant setting. As such, a significant proportion of patients with hormone receptor-positive MBC will have previously received tamoxifen, an AI or both, as adjuvant treatment. This has changed the metastatic landscape and has an impact on treatment choices for patients with hormone receptor-positive MBC. In this review, we evaluate the available evidence supporting the use of endocrine therapy for the treatment of hormone receptor-positive MBC. Additionally, we consider the effect of prior adjuvant therapy on treatment choice in the metastatic setting and the optimal treatment sequence. Finally, we discuss endocrine-responsive HER2 positive tumours and the ongoing research initiatives which aim to improve outcomes for patients with MBC.
Expression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare ...phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.
To compare the prevalence of contraception in breast cancer (BC) patients at risk of unintentional pregnancy (i.e. not currently pregnant or trying to get pregnant) and matched controls.
The FEERIC ...study (Fertility, Pregnancy, Contraception after BC in France) is a prospective, multicenter case-control study, including localized BC patients aged 18–43 years, matched for age and parity to cancer-free volunteer controls in a 1:2 ratio. Data were collected through online questionnaires completed on the Seintinelles research platform.
In a population of 1278 women at risk of unintentional pregnancy, the prevalence of contraception at study inclusion did not differ significantly between cases (340/431, 78.9%) and controls (666/847, 78.6%, p = 0.97). Contrarily, the contraceptive methods used were significantly different, with a higher proportion of copper IUD use in BC survivors (59.5% versus 25.0% in controls p < 0.001). For patients at risk of unintentional pregnancy, receiving information about chemotherapy-induced ovary damage at BC diagnosis (OR = 2.47 95%CI 1.39–4.37 and anti-HER2 treatment (OR = 2.46, 95% CI 1.14–6.16) were significantly associated with the use of a contraception in multivariate analysis.
In this large French study, BC survivors had a prevalence of contraception use similar to that for matched controls, though almost one in five women at risk of unintentional pregnancy did not use contraception. Dedicated consultations at cancer care centers could further improve access to information and contraception counseling.
Background
In older patients with cancer, comorbidities compete with cancer for cause of death. The objectives were to evaluate cancer mortality and factors associated, according to metastatic ...status.
Methods
Between 2007 and 2014, patients with cancer aged ≥70 referred for pre‐therapeutic geriatric assessment (GA) were included through the ELCAPA prospective cohort study. The underlying cause of death was defined according to the International Classification of Diseases, 10th Revision. The World Health Organisation definition was used to categorise the cause of death as cancer versus another disease (e.g. cardiovascular disease, infectious disease, etc.) Competing risk models were used.
Results
Mean (SD) age of the 1445 included patients was 80.2 (5.8) and 48% were women. Most common tumour sites were colorectal (19%), breast (17%) and urinary (15%); 773 patients (49%) had metastases. After a 34‐month median follow‐up, 706 cancer deaths were observed among 843 deaths. The 6‐month and 3‐year cancer mortality rates (95% CI) were 12% (9–15) and 34% (29–38) for non‐metastatic patients and 43% (39–47) and 79% (75–82) for metastatic patients, respectively. Dependency in activities of daily living and comorbidities were associated with 6‐month and 3‐year cancer mortality in non‐metastatic (adjusted subhazard ratio aSHR = 1.68 0.99–2.85 and 1.69 1.16–2.45; and 1.98 1.08–3.63 and 3.38 1.47–7.76, respectively) and metastatic patients (aSHR = 2.81 2.01–3.93 and 2.95 2.14–4.07; and 1.63 1.18–2.25 and 2.06 1.39–3.05, respectively). Impaired Timed‐Get‐Up‐and‐Go test was associated with 6‐month and 3‐year cancer mortality in metastatic patients (aSHR = 1.5 1.06–2.12 and 1.38 1.06–1.81, respectively). Obesity was negatively associated with 3‐year cancer death in non‐metastatic (aSHR = 0.53 0.29–0.97) and metastatic patients (aSHR = 0.71 0.51–1.00).
Conclusions
The majority of older adults with cancer referred for pre‐therapeutic GA die from cancer. Geriatric parameters are independently associated with cancer mortality and should be considered for prognosis assessment, decision‐making and care.
The majority of older adults with cancer referred for pre‐therapeutic GA died from cancer and not from other causes. An altered general status, loss of independency and co‐morbidities were independently associated with cancer death at 6 months and at 3 years, regardless of metastatic status; mobility impairment was independently associated with cancer death at 6 months and at 3 years in metastatic patients.
Background
More than 10% of HER2-positive metastatic breast cancer (mBC) will develop Central Nervous System (CNS) metastases as first and isolated site of relapse on trastuzumab and pertuzumab ...first-line therapy. However, few clinical data are available to guide the best strategy in this setting.
Methods
Patients experiencing isolated CNS progression on trastuzumab and pertuzumab first-line therapy were retrospectively identified from the French Epidemiological Strategy and Medical Economics (ESME) real-life database between 2008 and 2016.
Results
Among 995 patients treated with first-line trastuzumab and pertuzumab for HER2-positive mBC, 132 patients (13%) experienced isolated CNS progression with a median time of 12 months after mBC diagnosis. Twelves patients did not receive any treatment and were excluded from the analysis. Among the 120 patients considered, 76 (63%) received CNS-directed local therapy, 73 (60%) continued trastuzumab and pertuzumab, whereas 47 (39%) started another systemic treatment.
After a median follow-up of 21 months, there was no difference in progression-free survival for patient who continued trastuzumab–pertuzumab or switched to another systemic treatment. In multivariate analysis, trastuzumab–pertuzumab continuation was associated with longer OS (HR 0,28 IC 95%: 0,14–0,54
p
< 0,001). mOS was not reached (95% 37.6-NE) and was 23.2 months (95% CI 15.5–53.6) in patients who continued trastuzumab and pertuzumab therapy and in patients who switched for another systemic therapy, respectively.
Conclusion
In this real-life cohort, trastuzumab–pertuzumab continuation after local treatment for isolated CNS progression did not negatively impact PFS and OS. Prospective trials and assessment of new strategies are warranted in this specific situation.
Prognosis evaluation of advanced breast cancer and therapeutic strategy are mostly based on clinical features of advanced disease and molecular profiling of the primary tumor. Very few studies have ...evaluated the impact of metastatic subtyping during the initial metastatic event in a prospective study. The genomic landscape of metastatic breast cancer has mostly been described in very advanced, pretreated disease, limiting the findings transferability to clinical use.
We developed a multicenter, single-arm, prospective clinical trial in order to address these issues. Between November 2010 and September 2013, 123 eligible patients were included. Patients at the first, untreated metastatic event were eligible. All matched primary tumors and metastatic samples were centrally reviewed for pathological typing. Targeted and whole-exome sequencing was applied to matched pairs of frozen tissue. A multivariate overall survival analysis was performed (median follow-up 64 months).
Per central review in 84 patients (out of 130), we show that luminal A breast tumors are more prone to subtype switching. By combining targeted sequencing of a 91 gene panel (n = 67) and whole-exome sequencing (n = 30), a slight excess of mutations is observed in the metastases. Luminal A breast cancer has the most heterogeneous mutational profile and the highest number of mutational signatures, when comparing primary tumor and the matched metastatic tissue. Tumors with a subtype change have more mutations that are private. The metastasis-specific mutation load is significantly higher in late than in de novo metastases. The most frequently mutated genes were TP53 and PIK3CA. The most frequent metastasis-specific druggable genes were PIK3CA, PTEN, KDR, ALK, CDKN2A, NOTCH4, POLE, SETD2, SF3B1, and TSC2. Long-term outcome is driven by a combination of tumor load and metastasis biology.
Profiling of the first, untreated, metastatic event of breast cancer reveals a profound heterogeneity mostly in luminal A tumors and in late metastases. Based on this profiling, we can derive information relevant to prognosis and therapeutic intervention, which support current guidelines recommending a biopsy at the first metastatic relapse.
The trial was registered at ClinicalTrials.gov ( NCT01956552 ).
Five to 10% of breast cancers (BCs) occur in a genetic predisposition context (mainly
pathogenic variant). Nevertheless, little is known about immune tumor infiltration, response to neoadjuvant ...chemotherapy (NAC), pathologic complete response (pCR) and adverse events according to
status.
Out of 1199 invasive BC patients treated with NAC between 2002 and 2012, we identified 267 patients tested for a germline
pathogenic variant. We evaluated pre-NAC and post-NAC immune infiltration (TILs). Response to chemotherapy was assessed by pCR rates. Association of clinical and pathological factors with TILs, pCR and survival was assessed by univariate and multivariate analyses.
Among 1199 BC patients: 46 were
-deficient and 221
proficient or wild type (WT). At NAC completion, pCR was observed in 84/266 (31%) patients and pCR rates were significantly higher in
deficient BC (
0.001), and this association remained statistically significant only in the luminal BC subtype (
0.006). The interaction test between BC subtype and
status was nearly significant (
= 0.056). Pre and post-NAC TILs were not significantly different between
deficient and
proficient carriers; however, in the luminal BC group, post-NAC TILs were significantly higher in
deficient BC. Survival analysis were not different between
carriers and non-carriers.
mutation status is associated with higher pCR rates and post-NAC TILs in patients with luminal BC.
-carriers with luminal BCs may represent a subset of patients deriving higher benefit from NAC. Second line therapies, including immunotherapy after NAC, could be of interest in non-responders to NAC.
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