Abstract Aim Final 10-year analysis of the prospective randomised Chemo-N0 trial is presented. Based on the Chemo-N0 interim results and an European Organisation for Research and Treatment of Cancer ...(EORTC) pooled analysis ( n = 8377), American Society of Clinical Oncology (ASCO) and Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) guidelines recommend invasion and metastasis markers urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) for risk assessment and treatment decision in node-negative (N0) breast cancer (BC). Methods The final Chemo-N0 trial analysis (recruitment 1993–1998; n = 647; 12 centres) comprises 113 (5-167) months of median follow-up. Patients with low-uPA and PAI-1 tumour tissue levels ( n = 283) were observed. External quality assurance guaranteed uPA/PAI-1 enzyme-linked immunosorbent assay (ELISA) standardisation. Of 364 high uPA and/or PAI-1 patients, 242 agreed to randomisation for CMF chemotherapy ( n = 117) versus observation ( n = 125). Results Actuarial 10-year recurrence rate (without any adjuvant systemic therapy) for high-uPA/PAI-1 observation group patients (randomised and non-randomised) was 23.0%, in contrast to only 12.9% for low-uPA/PAI-1 patients ( plog-rank = 0.011). High-risk patients randomised to cyclophosphamide-methotrexate-5-fluorouracil (CMF) therapy had a 26.0% lower estimated probability of disease recurrence than those randomised for observation (intention-to-treat (ITT)-analysis: hazard ratio (HR) 0.74 (0.44–1.27); plog-rank = 0.28). Per-protocol analysis demonstrated significant treatment benefit: HR 0.48 (0.26–0.88), p = 0.019, disease-free survival (DFS) Cox regression, adjusted for tumour stage and grade. Conclusions Chemo-N0 is the first prospective biomarker-based therapy trial in early BC defining patients reaching good long-term DFS without adjuvant systemic therapy. Using a standardised uPA/PAI-1 ELISA, almost half of N0-patients could be spared chemotherapy, while high-risk patients benefit from adjuvant chemotherapy. These 10-year results validate the long-term prognostic impact of uPA/PAI-1 and the benefit from adjuvant chemotherapy in the high-uPA/PAI-1 group at highest level of evidence. They thus support the guideline-based routine use of uPA/PAI-1 for risk-adapted individualised therapy decisions in N0 breast cancer.
Guideline recommendations for the treatment of breast cancer with low hormone receptor (HR) expression (1%-9%) are ambiguous and several studies showed more similarities with HR-negative tumors than ...with HR strongly positive tumors (≥10%). We used a population-based 15-year cohort to compare patient characteristics and outcome of HR low positive tumors with HR-negative and HR strongly positive tumors, respectively.
A total of 38 560 women diagnosed with early invasive breast cancer between 2004 and 2018 within the scope of the Munich Cancer Registry with 4.9 million inhabitants were included. Descriptive analyses of prognostic factors, treatment, and outcome analyses using the Kaplan–Meier method; cumulative incidence in consideration of competing risks; and multivariate analyses (Cox regression and Fine–Gray model) were conducted. Endpoints were time to local recurrence (TTLR), time to lymph node recurrence (TTLNR), time to metastasis (TTM), overall survival (OS), and relative survival (RS).
A total of 861 patients (2%) had HR low positive, 4862 (13%) HR-negative, and 32 837 (85%) HR strongly positive tumors. Within the HER2-negative cohort (n = 33 366), survival of HR low positive tumors was significantly worse than that of HR strongly positive tumors OS hazard ratio 0.66 (95% confidence interval 0.55-0.78), whereas between HR low positive and HR-negative tumors no significant survival difference could be detected OS hazard ratio 0.93 (95% confidence interval 0.78-1.11). TTLR, TTLNR, and TTM showed similar results. By contrast, within the HER2-positive cohort (n = 5194), no statistically significant differences between the three HR groups could be detected in multivariate analyses.
Current definitions for HR positivity and its clinical relevance should be reconsidered. Patients with HR low positive/HER2-negative tumors could be regarded and treated similar to patients with triple-negative tumors.
•This study compared HR low positive tumors with HR-negative and HR strongly positive tumors, respectively.•In the HER2-negative cohort outcome of HR low positive tumors was similar to that of HR-negative tumors.•In the HER2-positive cohort no statistically significant differences were observed.•Current definitions for HR positivity and its clinical relevance should be reconsidered.•Patients with HR low pos./HER2-neg. tumors could be regarded and treated similar to patients with triple-negative tumors.
Physical activity (PA) helps prevention and aftercare of sporadic breast cancer (BC), cardiopulmonary fitness (CPF) being an age-independent predictor of tumor-specific mortality. Therefore, we ...wanted to identify predictors of CPF (represented by peak oxygen uptake: VO
) in BRCA1/2 mutation carriers whose risk of developing BC is high. We used cross-sectional data from 68 BRCA1/2 germline mutation carrying women participating in the randomized, prospective, controlled clinical study LIBRE-1. Assessments included cardiopulmonary exercise testing, medical and lifestyle history plus socioeconomic status. Additionally, the participants completed a psychological questionnaire regarding their attitude, subjective norms, perceived behavior control and intention towards PA. A multivariate logistic regression model was used to identify predictors for participants reaching their age- and sex-adjusted VO
reference values. 22 participants (median age: 40 years, interquartile range (IQR) 33-46) were cancer-unaffected and 46 cancer-affected (median age: 44 years, IQR 35-50). The strongest predictor for reaching the reference VO
value was attitude towards PA (Odds Ratio 3.0; 95% Confidence Interval 1.3-8.4; p = 0.021). None of the other predictors showed a significant association. A positive attitude towards PA seems to be associated with VO
, which should be considered in developing therapeutic and preventive strategies.Trial registrations: NCT02087592; DRKS00005736.
According to current treatment guidelines, comprehensive surgical staging procedures in endometrial cancer confined to the uterus depend on uterine risk factors: a systematic lymph node dissection ...(LND) is recommended in high risk patients and should be omitted in low risk patients. Its role in intermediate and high intermediate risk patients is inconclusive. The aim of this analysis was to review the implementation of this risk-adopted strategy.
Data were provided by the population-based Munich Cancer Registry. Patients with endometrial cancer diagnosed between 1998 and 2016 were included.
Of 5446 eligible patients, 58.5%, 30.1% and 11.4% belonged to the low risk, intermediate/high-intermediate and high risk group, respectively. Lymph node dissection was performed in 20.2%, 53.0% and 63.7% within these groups. Lymph node involvement was diagnosed in 1.7%, 9.6% and 19.3%, respectively. Within these risk groups, there was no significant difference in the time to local recurrence, lymph node recurrence or distant metastases between patients with and without LND. After adjusting for age and comorbidity-status, no significant difference in overall survival was found.
The application of a risk-adopted management of LND in early endometrial cancer in real-life is associated with a high rate of surgical under- and overtreatment. Corresponding survival data do not show a significant benefit of a systematic lymph node dissection. In order to improve the management and outcome of early endometrial cancer in the future, prospective trials, new surgical concepts and prognostic markers will be primary and necessary.
•Although it is recommended, a high proportion of patients had no lymph node surgery.•The incidence of recurrence seems not to be related to lymph node dissection.•The comorbidity status should be considered in analyses of lymph node surgery.•The survival analysis challenges lymph node dissection in endometrial cancer.
Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and ...cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1–3 positive lymph nodes (LNs) only.
A total of 2011 BC patients (18–65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors.
Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide) was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18–0.82) for EC-Doc versus FEC (test for interaction; P = 0.01).
EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1–3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy.
ClinicalTrials.gov, NCT02115204.
Obese breast cancer patients have a higher risk of lymph node metastasis and a poorer prognosis compared to patients with normal weight. For obese women with node-positive breast cancer, an ...association between body weight and prognosis remains unclear. In this retrospective study, we analyzed patient data from the Phase-III ADEBAR trial, in which high-risk breast cancer patients (pT1–4, pN2–3, pM0) were randomized into a docetaxel-based versus epirubicin-based chemotherapy regimen. Patients were grouped according to their BMI value as underweight/normal weight (BMI < 25 kg/m
2
;
n
= 543), overweight (BMI 25–29.9 kg/m
2
;
n
= 482) or obese (BMI ≥ 30 kg/m
2
;
n
= 285). Overweight and obese patients were older, had larger tumors and were more likely to be postmenopausal at the time of diagnosis compared to underweight/normal-weight patients (all
p
< 0.001). Multivariate Cox regression analyses adjusting for age and histopathological tumor features showed that obese patients had a significantly shorter disease-free survival (DFS; HR 1.43; 95 % CI 1.11–1.86;
p
= 0.006) and overall survival (OS; HR 1.56; 95 % CI 1.14–2.14;
p
= 0.006) than non-obese patients. Subgroup analyses revealed that the differences in DFS and OS were significant for postmenopausal but not for premenopausal patients, and that the survival benefit of non-obese patients was more pronounced in women with hormone-receptor-positive disease. Obesity constitutes an independent, adverse prognostic factor in high-risk node-positive breast cancer patients, in particular for postmenopausal women and women with hormone-receptor-positive disease.
Kallikrein-related peptidases (KLK), which represent a major tissue-associated proteolytic system, stand for a rich source of biomarkers that may allow molecular classification, early diagnosis and ...prognosis of human malignancies as well as prediction of response or failure to cancer-directed drugs. International research points to an important role of certain KLKs in female and male urogenital tract malignancies, in addition to cancers of the lung, brain, skin, head and neck, and the gastrointestinal tract. Regarding the female/male urogenital tract, remarkably, all of the KLKs are expressed in the normal prostate, testis, and kidney whereas the uterus, the ovary, and the urinary bladder are expressing a limited number of KLKs only. Most of the information regarding KLK expression in tumour-affected organs is available for ovarian cancer; all of the 12 KLKs tested so far were found to be elevated in the malignant state, depicting them as valuable biomarkers to distinguish between the normal and the cancerous phenotype. In contrast, for kidney cancer, a series of KLKs was found to be downregulated, while other KLKs were not expressed. Evidently, depending on the type of cancer or cancer stage, individual KLKs may show characteristics of a Janus-faced behaviour, by either expanding or inhibiting cancer progression and metastasis.
Primary tumor levels of serine proteases of the kallikrein-related peptidases (KLK) family as well as urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 impact disease course in ...ovarian cancer. The changes in levels of these factors from primary tumor to omentum metastasis (‘level differentials’) could thus be associated with metastastic processes.
Protein levels of seven tissue KLK (KLK5–8, 10, 11, 13), uPA, and PAI-1 were determined in extracts of primary tumor tissue and corresponding omentum metastasis of 54 ovarian cancer patients.
Higher level differentials of KLK5–8, 10–11, and uPA were associated with residual tumor >10 mm. Residual tumor and larger level differentials of KLK5–7, 10, and uPA were associated with disease progression in the whole cohort. Remarkably, level differentials of KLK5–8 and 10–11 strongly impacted disease progression even in patients with residual tumor mass ≤10 mm; hence, the observed impact of level differentials in KLK5–7 and 10 on disease progression was not simply attributable to their association with surgical success.
Since they impact both surgical outcome and survival in advanced ovarian cancer, measurement of level differentials could support clinical decisions on surgical and systemic therapy or help in patient selection for novel targeted therapies.
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