Evaluation of early breast cancer treatment effects and prognostic factors with special reference to steroid and HER2 receptors

Wstęp. Dobór leczenia uzupełniającego chorych na wczesnego raka piersi po operacji oszczędzającej zależy od wielu czynników prognostycznych, a szczególnie od układu receptorów steroidowych (URS) i HER2. Celem pracy jest ocena skuteczności leczenia chorych poprzez zbadanie przeżycia bezobjawowego (PB) i ryzyka nawrotu lokoregionalnego raka piersi, jak również analiza wpływu klasycznych czynników prognostycznych z uwzględnieniem URS i HER2 na PB chorych przed erą leczenia trastuzumabem. Materiał i metoda. Badaniem objęto kolejnych 615 kobiet chorych na wczesnego inwazyjnego raka piersi leczonych metodą oszczędzającą w Centrum Onkologii w Warszawie w latach 2003–2006. U 40% chorych stosowano uzupełniającą chemioterapię drugiej i trzeciej generacji, a u 28% hormonoterapię. Po operacji i zakończeniu chemioterapii stosowano radioterapię piersi metodą hipofrakcjonacji dawki w czasie 3–4 tygodni. W badaniu uwzględniono następujące czynniki prognostyczne: wiek chorych, stan hormonalny, strona leczonej piersi, pT, pN, typ histopatologiczny raka, G, obecność komponentu raka przedinwazyjnego w raku inwazyjnym, rozmiar marginesów wokół usuniętego guza i 4 podtypy raka piersi różniące się URS i HER2 — luminalny (ER dodatni i/lub PGR dodatni) HER2 ujemny, luminalny (ER dodatni i/lub PGR dodatni) HER2 dodatni, trójujemny i nieluminalny (ER ujemny i/lub PGR ujemny) HER2 dodatni. W analizie statystycznej krzywe przeżycia obliczano metoda Kaplana-Meiera, do oceny ryzyka nawrotu wykorzystano metodę konkurujących ryzyk, a czynniki prognostyczne badano w modelu proporcjonalnego ryzyka Coxa. Mediana obserwacji wynosiła 8 lat. Wyniki. Prawdopodobieństwo 8-letniego przeżycia bezobjawowego i ryzyko nawrotu lokoregionalnego wyniosły odpowiednio: 89%; 4,6%. Potwierdzono negatywny wpływ na ryzyko niepowodzenia w leczeniu raka piersi dla następujących czynników prognostycznych: młodego wieku, liczby zajętych przez przerzuty węzłów chłonnych (powyżej trzech) i niskiego stopnia zróżnicowania raka (G3). Nie stwierdzono istotnego statystycznie wpływu podtypów biologicznych na skuteczność leczenia ani w analizie jednoczynnikowej, ani wieloczynnikowej — test log-rank p = 0,19. Wykazano jednakże występowanie ujemnego trendu prawdopodobieństwa przeżycia bez niepowodzenia dla podtypów biologicznych w następującym porządku: luminalny HER2 (ujemny), luminalny HER2 (dodatni), trójujemny i nieluminalny HER2 (dodatni) — test log-rank dla trendu p = 0,03). Analiza rozkładu badanych czynników prognostycznych potwierdziła, że u chorych w podtypie biologicznym trójujemnym i neluminalnym HER2 (dodatnim) znamiennie częściej niż w typach luminalnym HER2 (ujemnym) i luminalnym HER2 (dodatnim), stwierdza się młodsze chore, z większym guzem, i większą niż 3 liczbą węzłów chłonnych z przerzutami w jamie pachowej i z częstszym rozpoznawanym rakiem niskozróżnicowanym G3. Wnioski. 1. Wysokie prawdopodobieństwo 8-letniego przeżycia bezobjawowego chorych i niskie ryzyko nawrotu lokoregionalnego raka piersi upoważnia do pozytywnej oceny leczenia oszczędzającego w Centrum Onkologii w latachIntroduction. Choice of adjuvant systemic therapy in early breast cancer patients followed breast conserving surgery depends on many prognostic factors especially from steroid (estrogen receptor — ER; progesterone receptor — PR) and HER-2 receptor status. Purpose. To evaluate the treatment we determined disease free survival (DFS) and the risk of local recurrence and examined the influence of classical prognostic factors with special consideration of the biological subtype of breast cancer on DFS before the era of trastuzumab treatment. Patients and methods. Consecutively 615 female patients with early invasive breast cancer received breast conservative treatment between 2003 and 2006 in the Oncological Center in Warsaw. Data were prospectively collected. Adjuvant systemic therapy of second and third generation in 40% of patients had been given and in 28% of patients hormonotherapy was applied. After surgery and chemotherapy, irradiation with mild hypofractionation during 3 or 4 weeks was used. The following prognostic factors were included in the study: age, menopausal status, breast laterality, pT, pN, histology, grade, EIC, margins, and four biological subtypes: Luminal (ER positive and/or PR positive) HER-2 negative, Luminal (ER positive and/or PR positive) HER-2 positive, Triple-Negative, Non-Luminal (ER positive and/or PR positive) HER-2 positive. Survival curves were obtained using the Kaplan Maier method. To analyse time to recurrence, the competing risk method was performed. To study the influence of prognostic factors on DFS the proportional hazards model of Cox was used. The median follow-up time was 8 years. Results. The 8-year DFS and cumulative loco-regional recurrence (CLRR) rate were 89% and 4.6% respectively. The significant factors influencing DFS were: young age of patients, number of involved nodes above three and grade 3 histological malignancy. Biological subtypes of breast cancer were not significant predictors for DFS in the univariate or multivariate analysis — logrank test: p = 0.19. It was shown, however, the probability of occurrence of the negative trend DFS for biological subtypes in the following order: Luminal HER2 (negative), Luminal HER2 (positive), Triple-negative and Nonluminal HER2 (positive) — logrank test for trend: p = 0.03. The analysis examined the distribution of prognostic factors and confirmed that in biological subtype Triple-negative and Nonluminal HER2 (positive) significantly more often than in the types of Luminal HER2 (negative) and Luminal HER2 (positive), were younger patients, with larger tumour, with more than 3 involved nodes and grade 3 histological malignancy. Conclusions. 1. High probability of 8-year DFS and low CLRR rate of breast cancer indicated a positive assessment of conserving therapy at the Cancer Center in Warsaw between 2003–2006. 2. Despite aggressive treatment the strongest prognostic factors still remain: the young age of patients, the number of involved lymph node in the axillary fossa greater than three and low differentiation of cancer G3. 3. The worst prognosis is for patients diagnosed with breast cancer in subtype Nonluminal HER2 (positive), and this justifies the introduction of molecular targeted therapies aimed at HER2.

Kinetics of selected serum markers of fibrosis in patients with dilated cardiomyopathy and different grades of diastolic dysfunction of the left ventricle

Background: Fibrosis of the extracellular matrix (ECM) in dilated cardiomyopathy (DCM) is common and compromises both systolic and diastolic function. The aim of this study was to investigate the kinetics of ECM fibrosis markers over a 12 month follow-up in patients with DCM based on the severity of diastolic dysfunction (DD).Methods: Seventy consecutive DCM patients (48 ± 12.1 years, ejection fraction 24.4 ± 7.4%) were included in the study. The grade of DD was determined using the ASE/EACVI algorithm. Markers of ECM fibrosis were measured at baseline and at 3 and 12 month follow-ups: collagen type I and III (PICP, PINP, PIIICP, PIIINP), transforming growth factor beta-1 (TGF1-b), connective tissue growth factor (CTGF) and galectin-3 were measured.Results: Patients were divided into three groups according to DD severity: 30 patients with grade I, 18 with grade II and 22 with grade III of DD. Levels of PICP, PINP were increased over a 12-month period, while PIIINP decreased and PIIICP unchanged. Levels of TGF1-b decreased from the 3 to the 12-month points in grade I and II DD, and in grade III they remained unchanged. Levels of CTGF decreased over 12 months in grade III DD but were unchanged in grades I and II. Galectin-3 levels remained the same over all observation periods, irrespective of DD grade.Conclusions: Regardless of the DD grade, markers of collagen type I synthesis increased, markers of collagen type III decreased. Levels of TGF and CTGF had a tendency to decrease. Galectin-3 was revealed not to be a marker discriminating the severity of DD

Relationships between pulmonary hypertension risk, clinical profiles, and outcomes in dilated cardiomyopathy

Pulmonary hypertension (PH) in patients with heart failure (HF) contributes to a poorer prognosis. However, in those with dilated cardiomyopathy (DCM), the true prevalence and role of PH is unclear. Therefore, this study aimed to analyze the profile of DCM patients at various levels of PH risk, determined via echocardiography, and its impact on outcomes. The 502 DCM in- and out-patient records were retrospectively analyzed. Information on patient status was gathered after 45.9 ± 31.3 months. Patients were divided into 3 PH-risk groups based on results from echocardiography measurements: low (L, n = 239, 47.6%), intermediate (I, n = 153, 30.5%), and high (H, n = 110, 21.9%). Symptom duration, atrial fibrillation, ventricular tachyarrhythmia, ejection fraction, right atrial area, and moderate or severe mitral regurgitation were found to be independently associated with PH risk. During the follow-up period, 83 (16.5%) DCM patients died: 29 (12.1%) in L, 31 (20.3%) in I, and 23 (20.9%) in H. L-patients had a significantly lower risk of all-cause death (L to H: HR 0.55 (95%CI 0.32–0.98), p = 0.01), while no differences in prognosis were found between I and H. In conclusion, over one in five DCM patients had a high PH risk, and low PH risk was associated with better prognoses