Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from ...single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.
Several expression array studies identified molecular apocrine breast cancer (BC) as a subtype that expresses androgen receptor (AR) but not estrogen receptor α. We carried out a multicentre ...single-arm phase II trial in women with AR-positive, estrogen, progesterone receptor and HER2-negative (triple-negative) metastatic or inoperable locally advanced BC to assess the efficacy and safety of abiraterone acetate (AA) plus prednisone.
Patients with a metastatic or locally advanced, centrally reviewed, triple-negative and AR-positive (≥10% by immunohistochemistry, IHC) BC were eligible. Any number of previous lines of chemotherapy was allowed. AA (1000 mg) was administered once a day with prednisone (5 mg) twice a day until disease progression or intolerance. The primary end point was clinical benefit rate (CBR) at 6 months defined as the proportion of patients presenting a complete response (CR), partial response (PR) or stable disease (SD) ≥6 months. Secondary end points were objective response rate (ORR), progression-free survival (PFS) and safety.
One hundred and forty-six patients from 27 centres consented for IHC central review. Of the 138 patients with sufficient tissue available, 53 (37.6%) were AR-positive and triple-negative, and 34 of them were included from July 2013 to December 2014. Thirty patients were eligible and evaluable for the primary end point. The 6-month CBR was 20.0% 95% confidence interval (CI) 7.7%–38.6%, including 1 CR and 5 SD ≥6 months, 5 of them still being under treatment at the time of analysis (6.4+, 9.2+, 14.5+, 17.6+, 23.4+ months). The ORR was 6.7% (95% CI 0.8%–22.1%). The median PFS was 2.8 months (95% CI 1.7%–5.4%). Fatigue, hypertension, hypokalaemia and nausea were the most common drug-related adverse events; the majority of them being grade 1 or 2.
AA plus prednisone treatment is beneficial for some patients with molecular apocrine tumours and five patients are still on treatment.
NCT01842321.
Chemotherapy (CT) remains a backbone treatment of epithelial ovarian cancer (EOC) inducing persistent peripheral neuropathy (CIPN). Using a dedicated patient-reported outcome tool, this study ...investigated persistent CIPN and its pharmacogenetic predictors in a cohort of long-term EOC survivors.
Vivrovaire was a French multicenter cohort of patients with EOC free of disease 3 years after CT completion. Persistent CIPN was assessed using the FACT/GOG-Ntx4 self-questionnaire. The association of homozygous (hom) or heterozygous (het) single nucleotide polymorphisms (SNPs) in selected genes was evaluated.
130 patients were included with a median time from CT completion of 63 35–180 months. The median CIPN score was 37 18–44, with 35 (26.9%) patients reporting severe CIPN (<33). SNPs were identified as follows: CYP2C8 hom, n = 32 (24.6%)/het, n = 99, (76.2%); CYP3A4 hom, n = 0 (0%)/het, n = 8 (6.2%), ERCC1 hom, n = 21 (16.2%)/het, n = 57 (43.8%), and XPC hom, n = 45 (34.6%)/het, n = 66 (50.8%). In univariate analysis, the identification of ≥1 hom SNP was associated with a lower CIPN score (continuous variable; p = 0.045). Patients harboring hom or het CYP2C8_rs1934951 SNP reported more likely severe CIPN (threshold <33) score (OR 2.482; 95% CI 1.126–5.47, p = 0.024). In the multivariate analyses, age, interval from CT completion, type and number of CT courses were not significantly associated with CIPN score (OR 5.165, 95% CI 0.478–55.83, p = 0.176).
Persistent CIPN is common among ovarian cancer long-term survivors. CYP2C8_rs1934951 SNP may be associated with severe residual CIPN in EOC survivors. More studies are warranted to identify predictive factors of CIPN.
•CIPN is a common concern in ovarian cancer survivors.•Using a PRO tool, about 25% of patients report persistent severe CIPN.•CYP2C8_rs1934951 SNP may be associated with a severe long-term CIPN.
Two previous GINECO elderly specific studies in advanced ovarian cancer (AOC) patients highlighted the prognostic value of geriatric covariates for overall survival (OS).
This open-label prospective ...trial was designed to identify the impact of geriatric covariates on OS in AOC patients ≥70 years treated with first-line carboplatin.
Geriatric covariates of the 111 patients included median age 79 years (≥80 years: 41%); performance status (PS) ≥2: 47%; ≥3 major comorbidities: 24%; ≥4 comedications: 68%; activities of daily living (ADL) score <6: 55%; instrumental activities of daily living (IADL) score <25: 69%; Hospital Anxiety and Depression Scale (HADS) >14: 37%. The median OS was 17.4 months. Overall, 74% of patients completed the six planned chemotherapy cycles. Grade 3–4 haematological toxic effects were frequent (50%) but manageable. Grade 3–4 non-haematological toxicities included fatigue (15%), anorexia (12%), infections (9%) and thrombosis (2%). A survival score = exp(0.327*GVS) was developed, where the geriatric vulnerability score (GVS) is the sum of the following (each assigned a value of one): albuminaemia <35 g/l; ADL score <6; IADL score <25; lymphopaenia <1 G/l; and HADS >14. With a cut-off ≥3, GVS discriminated two groups with significantly different OS, treatment completion, severe adverse events and unplanned hospital admissions rates.
The GVS is a valuable tool for identifying vulnerable patients when treating an elderly AOC population.
We aimed to generate a model of cancer-related fatigue (CRF) of clinical importance two years after diagnosis of breast cancer building on clinical and behavioral factors and integrating ...pre-treatment markers of systemic inflammation.
Women with stage I-III HR+/HER2- breast cancer were included from the multimodal, prospective CANTO cohort (NCT01993498). The primary outcome was global CRF of clinical importance (EORTC QLQ-C30≥40/100) two years after diagnosis (year-2). Secondary outcomes included physical, emotional, and cognitive CRF (EORTC QLQ-FA12). All pre-treatment candidate variables were assessed at diagnosis, including inflammatory markers (interleukin IL-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, interferon gamma, IL-1 receptor antagonist, TNF-α, and C-reactive protein), and were tested in multivariable logistic regression models implementing multiple imputation and validation by 100-fold bootstrap resampling.
Among 1208 patients, 415 (34.4%) reported global CRF of clinical importance at year-2. High pre-treatment levels of IL-6 (Quartile 4 vs.1) were associated with global CRF at year-2 (adjusted Odds Ratio aOR: 2.06 95% Confidence Interval 1.40-3.03; p=0.0002; AUC=0.74). Patients with high pre-treatment IL-6 had unhealthier behaviors, including being frequently either overweight or obese (62.4%; mean BMI 28.0 SD 6.3 Kg/m2) and physically inactive (53.5% did not meet WHO recommendations). Clinical and behavioral associations with CRF at year-2 included pre-treatment CRF (aOR vs no: 3.99 2.81-5.66), younger age (per 1-year decrement: 1.02 1.01-1.03), current smoking (vs never: 1.81 1.26-2.58), and worse insomnia or pain (per 10-unit increment: 1.08 1.04-1.13, and 1.12 1.04-1.21, respectively). Secondary analyses indicated additional associations of IL-2 (aOR per log-unit increment:1.32 CI 1.03-1.70) and IL-10 (0.73 0.57-0.93) with global CRF and of C-reactive protein (1.42 1.13-1.78) with cognitive CRF at year-2. Emotional distress was consistently associated with physical, emotional, and cognitive CRF.
This study proposes a bio-behavioral framework linking pre-treatment systemic inflammation with CRF of clinical importance two years later among a large prospective sample of survivors of breast cancer.
•34.4% of 1208 stage I-III breast cancer survivors had cancer-related fatigue of clinical importance 2 years after diagnosis•High pre-treatment levels of the pro-inflammatory cytokine IL-6 were associated with global fatigue 2 years later•Individuals with high levels of IL-6 had higher body mass index and were less physically active than those with lower levels•Higher pre-treatment IL-2 and IL-10 were also associated with higher and lower likelihood of global fatigue, respectively•Higher C-reactive protein was associated with higher likelihood of cognitive fatigue
Few data are available on long-term fatigue (LTF) and quality of life (QoL) among epithelial ovarian cancer survivors (EOCS). In this case–control study, we compared LTF, symptoms and several QoL ...domains in EOCS relapse-free ≥3years after first-line treatment and age-matched healthy women.
EOCS were recruited from 25 cooperative GINECO centers in France. Controls were randomly selected from the electoral rolls. All participants completed validated self-reported questionnaires: fatigue (FACIT-F), QoL (FACT-G/O), neurotoxicity (FACT-Ntx), anxiety/depression (HADS), sleep disturbance (ISI), and physical activity (IPAQ). Severe LTF (SLTF) was defined as a FACIT-F score <37/52. Univariate and multivariate logistic regressions were conducted to analyze SLTF and its influencing factors in EOCS.
A total of 318 EOCS and 318 controls were included. EOCS were 63-year-old on average, with FIGO stage I/II (50%), III/IV (48%); 99% had received platinum and taxane chemotherapy, with an average 6-year follow-up. There were no differences between the two groups in socio-demographic characteristics and global QoL. EOCS had poorer FACIT-F scores (40 versus 45, P<0.0001), lower functional well-being scores (18 versus 20, P=0.0002), poorer FACT-O scores (31 versus 34 P<0.0001), and poorer FACT-Ntx scores (35 versus 39, P<0.0001). They also reported more SLTF (26% versus 13%, P=0.0004), poorer sleep quality (63% versus 47%, P=0.0003), and more depression (22% versus 13%, P=0.01). Fewer than 20% of EOCS and controls exercised regularly. In multivariate analyses, EOCS with high levels of depression, neurotoxicity, and sleep disturbance had an increased risk of developing SLTF (P<0.01).
Compared with controls, EOCS presented similar QoL but persistent LTF, EOC-related symptoms, neurotoxicity, depression, and sleep disturbance. Depression, neuropathy, and sleep disturbance are the main conditions associated with severe LTF.
We have previously shown that epithelial ovarian cancer (EOC) and its treatments have negative effects on long-term quality of life (QoL) and fatigue. The present multicenter study investigated the ...main menopausal symptoms and gynecological management of EOC survivors (EOCS).
166 patients with relapse-free ≥3 years after the end of treatment attended a consultation with a gynecologist, including a questionnaire related to vasomotor symptoms (VMS) and sexuality, a clinical examination, a blood sample and an osteodensitometry. QoL, fatigue, insomnia and mood disorders were measured with validated questionnaires and correlated to VMS. VMS and QoL were assessed according to natural menopause (NM) or surgical menopause (SM).
Mean age at the survey was 62 21–83 years and stage III/IV (48%). Mean delay since the end of treatment was 6 years. Fifty-nine patients (36%) had SM. Half of patients reported VMS. Seventy-two percent of EOCS with SM had VMS compared to 41% with NM (P < .001). VMS were not associated with poor global QoL, fatigue, insomnia or mood disorders. Two-thirds of EOCS reported a decrease in libido. Patients with SM showed a greater decrease in libido than NM (P < .02). Fourteen percent of them had osteoporosis and 50% osteopenia. Among the 85 patients with VMS, 80 did not receive HRT after cancer treatment. At the time of the survey, only 7 (4%) patients were receiving hormone replacement therapy (HRT).
VMS and sexual disorders are frequently reported by EOCS, particularly among patients with SM. Most EOCS with menopausal symptoms could benefit from HRT to improve these symptoms.
•≥3 years after treatment, more than half of epithelial ovarian cancer survivors EOCS had vasomotor symptoms.•Two thirds of the EOCS reported a decrease in libido and, 1/3 sexually active EOCS complained of dyspareunia.•EOCS with surgical menopause reported more vasomotor symptoms and sexual disorders than those with natural menopause.•Very few patients received hormone replacement therapy after cancer treatment.
Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors for some of which the epithelial growth factor receptor (EGFR) pathway may play an important role. We investigated the efficacy ...and toxicity of an anti-EGFR antibody (panitumumab) combined with a standard neoadjuvant anthracycline–taxane-based chemotherapy in patients with operable, stage II–III, TNBC.
Treatment in this multicentric neoadjuvant pilot study consisted of panitumumab (9mg/kg) for eight cycles q.3 weeks combined with four cycles of 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC100: 500/100/500mg/m2) q.3 weeks, followed by four cycles of docetaxel (T: 100mg/m2) q.3 weeks. Following therapy, all patients underwent surgical resection. Pathologic complete response (pCR) in assessable patients was the main end point while clinical response, toxicity and ancillary studies were secondary end points. Paraffin-embedded and frozen tumor samples were systematically collected with the aim to identify predictive biomarkers of efficacy and resistance in order to select biologically defined subpopulations for potential further clinical development of the anti-EGFR antibody.
Sixty patients were included with 47 assessable for pathologic response. The pCR rates were 46.8% 95% confidence interval (CI): 32.5% to 61.1% and 55.3% 95% CI: 41.1% to 69.5% according, respectively, to Chevallier and Sataloff classifications. The complete clinical response (cCR) rate was 37.5%. Conservative surgery was carried out in 87% of cases. Toxicity was manageable. The association of high EGFR and low cytokeratin 8/18 expression in tumor cells on one hand and high density of CD8+ tumor-infiltrating lymphocytes on the other hand were significantly predictive of pCR.
Panitumumab in combination with FEC100 followed by docetaxel appears efficacious, with acceptable toxicity, as neoadjuvant therapy of operable TNBC. Several biomarkers could help define large subsets of patients with a high probability of pCR, suggesting a potential interest to further develop this combination in biologically defined subgroups of patients with TNBC.
NCT00933517.
Background
Genomic tests are a useful tool for adjuvant chemotherapy decision‐making in the case of hormone receptor‐positive (HR+), and human epidermal growth factor receptor 2‐negative (HER2−) ...breast cancer with intermediate prognostic factors. Real‐life data on the use of tests can help identify the target population for testing.
Methods
French multicentric study (8 centers) including patients, all candidates for adjuvant chemotherapy for HR‐positive, HER2‐negative early breast cancer. We describe the percentage of tests performed outside recommendations, according to the year of testing. We calculated a ratio defined as the number of tests required to avoid chemotherapy for one patient, and according to patient and cancer characteristics. We then performed a cost‐saving analysis using medical cost data over a period of 1 year from diagnosis, calculated from a previous study. Finally, we calculated the threshold of the ratio (number of tests required to avoid chemotherapy for one patient) below which the use of genomic tests was cost‐saving.
Results
A total of 2331 patients underwent a Prosigna test. The ratio (performed test/avoided chemotherapy) was 2.8 95% CI: 2.7–2.9 in the whole population. In the group following recommendations for test indication, the ratio was 2.3 95% CI: 2.2–2.4. In the case of non‐abidance by recommendations, the ratio was 3 95% CI: 2.8–3.2. Chemotherapy was avoided in 841 patients (36%) following the results of the Prosigna test. The direct medical costs saved over 1 year of care were 3,878,798€ and 1,718,472€ in the group of patients following test recommendations. We calculated that the ratio (performed test/avoided chemotherapy) needed to be under 6.9 for testing to prove cost‐saving.
Conclusion
The use of genomic testing proved cost‐saving in this large multicentric real‐life analysis, even in certain cases when the test was performed outside recommendations.
PDF
