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Ea6f9582ed64b57a580ac479dfa Acta Clin Croat 2020; 59:97-108 Original Scientific Paper doi: 10.20471/acc.2020.59.01.12 CHARACTERISTICS AND PROGNOSIS OF TRIPLE-NEGATIVE BREAST CANCER PATIENTS: A CROATIAN SINGLE INstitUtion RETROSPECTIVE COHORT STUDY Ana Tečić Vuger1, Robert Šeparović1,5, Ljubica Vazdar1, Mirjana Pavlović1, Petra Lepetić1, Sanda Šitić2, Žarko Bajić3, Božena Šarčević4 and Damir Vrbanec5 1Department of Medical Oncology, Division of Radiotherapy and Medical Oncology, University Hospital for Tumors, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 2Department of Oncologic Cytology and Pathology, University Hospital for Tumors, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 3Dr. Mirko Grmek Scientific Unit, Sveti Ivan Psychiatric Hospital, Zagreb, Croatia; 4School of Medicine, University of Zagreb, Zagreb, Croatia; 5School of Medicine, Juraj Dobrila University, Pula, Croatia SUMMARY – Triple-negative breast cancer (TNBC) occurs in around one-sixth of all breast cancer (BC) patients, with the most aggressive behavior and worst prognosis of all BC subtypes. It is a heterogeneous disease, with specific molecular characteristics and natural dynamics of early recur- rence and fast progression. Due to the lack of biomarkers or any valid treatment targets, it can only be treated with classic cytotoxic chemotherapy. We analyzed a cohort of 152 patients, median age 58 years, diagnosed with and treated for early stage TNBC at the University Hospital for Tumors, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia, during the 2009-2012 period. Patients were treated with primary surgical approach, adjuvant chemotherapy and adjuvant irradiation. We observed a relatively large proportion of locally advanced TNBC at diagnosis, with large tumor size and nodal involvement, with high grade and high proliferation index Ki67. Patient age, tumor size and lymph node involvement, as expected, were significant and clinically most important prognostic factors for 5-year disease-free survival (67%; 95% CI 60%-75%) and overall absolute survival rate (74%; 95% CI 66%-81%). Key words: Triple negative breast cancer; Early disease; Adjuvant treatment; Tumor size; Lymph node; Disease free survival; Overall survival; Prognostic factor Introduction of BC: luminal A (LA), luminal B (LB), HER2 en- riched, and basal-like type1. The goal of classifying BC Molecular profiling has shown that breast cancer is to better understand the biology and to identify bio- (BC) is a heterogeneous disease. According to gene markers for therapeutic decision. In practice, we use expression, there are four essential, intrinsic subtypes immunostaining to detect three biomarkers, ER, PR and HER2, at protein level. Based on their expression, Correspondence to: Ana Tečić Vuger, MD, Department of Medical as well as expression of Ki67, we use surrogate sub- Oncology, Division of Radiotherapy and Medical Oncology, Uni- types to guide our therapeutic decision, as follows: lu- versity Hospital for Tumors, Sestre milosrdnice University Hospital Centre, Ilica 197, HR-10000 Zagreb, Croatia minal A-like, luminal B-like (HER2 positive and E-mail: [email protected] HER2 negative), nonluminal HER2 positive, and tri- Received December 30, 2019, accepted February 18, 2020 ple-negative BC (TNBC). These are four prognosti- Acta Clin Croat, Vol. 59, No. 1, 2020 97 Ana Tečić Vuger et al. Triple-negative breast cancer cally different entities, diseases that behave differently, currence, a particular tendency to deliver distant, vis- respond differently to therapy, and have different sur- ceral metastases, most commonly to the lungs and vival outcome2, with luminal subtypes, especially lumi- brain, rapid progression and short time from the ap- nal A being the subtype with indolent disease and pearance of distant metastases to death19,20. The de- good outcome, and the TNBC subtype with very few scribed dynamics of TNBC has been observed within therapeutic options and poor outcome3. Histologically, the first 3 to 5 years of the diagnosis, after which the TNBC is in most cases invasive ductal carcinoma but risk of disease recurrence and the rate of return and may also be one of the rarer histologic subtypes such as dissemination of disease are equated with those ob- apocrine or adenoid cystic, with better prognosis4. served in other BC subtypes, which have a lower and TNBC was first mentioned in the literature in 20055, more uniform risk of disease recurrence over a longer and since then, thousands of scientific papers have period of time23. There is no effect of endocrine thera- been published covering different aspects of TNBC. py or targeted anti-HER2 therapy in TNBC. The Since it is a highly heterogeneous disease, different backbone of TNBC treatment is still classic cytotoxic subtypes of TNBC have different genetic basis, phe- therapy. The optimal chemotherapy approach to notypic expression, different behavior, different re- TNBC has not been defined and the treatment prin- sponse to therapy and prognosis6. TNBC can be fur- ciples used in other types of BC are also used in ther reclassified according to gene expression, DNA TNBC, with the fact that TNBC is much more likely and RNA changes observed, expression of proteins on to have more risk factors present that influence thera- tumor cell, and immune potential7-10. One of the first peutic decision24. TNBC shows high rates of patho- comprehensive molecular profilings of TNBC was logic complete response (pCR) to neoadjuvant che- Lehmann’s categorization into six TNBC subtypes, as motherapy (NAT), and when pCR is achieved, the follows: basal-like 1 (BL1), basal-like 2 (BL2), mesen- long-term overall survival (OS) is often good. How- chymal (M), mesenchymal stem-like (MSL), luminal ever, in cases where pCR is not achieved, the prognosis AR type (LAR), and immunomodulatory type (IM)11. of TNBC is very poor and significantly worse than in 21,25 This characterization has been further modified by other types of BC . In systemic approach, chemo- Burstein and Lehmann himself into four subtypes of therapy based on anthracyclines and taxanes is most 26,27 TNBC, i.e. two basal-like types, immunoactivated and commonly used , and the use of other drugs such as immunosuppressed, mesenchymal and luminal andro- platinum compounds has been shown to be effective, gen receptor (LAR) type12,13. In practice, TNBC and especially in the treatment of BRCA mutated 26,28 basal-like BC are often considered synonyms for the TNBC .Capecitabine is also often used as adjuvant 29 same entity, but based on the scientific data available, treatment, if NAT failed to provide pCR . In addition there is a substantial but not complete overlap14-16. to conventional cytotoxic therapy, some targeted ther- TNBC occurs in about 12%-17% of BC, most com- apies have also been attempted, and poly(ADP-ribose) monly in younger women, often BRCA mutation car- polymerase (PARP) inhibitors are showing very en- 30-33 riers, or sporadically, and is characterized by aggressive couraging results in metastatic setting . A certain nature17. Epigenetic changes are also often present in proportion of TNBC express androgen receptors, which 34 the BRCA genes of sporadically developed, nonhe- are an attractive therapeutic target . In recent years, reditary TNBC18. TNBC are mostly poorly differenti- there has been a growing interest in the immunogenic- ated tumors of high mitotic index, more often involv- ity of TNBC and immunotherapy as a new, potentially ing lymph nodes and lymphovascular spaces, and successful therapeutic approach. Data in the metastat- 35 growing faster. Due to these aggressive characteristics, ic setting are strongly proposing survival impact , and they are more sensitive to chemotherapy and evidently the lately results of neoadjuvant experience also direct 36 respond better compared to other BC subtypes3,19-21. the interest towards the immunologic arsenal . However, despite better initial responses to therapy re- The primary objective of our study was to identify ported, the end outcomes in treating TNBC are much the prognostic factors associated with TNBC out- worse than in other BC subtypes, a phenomenon come. Secondary objectives were to describe the char- known as the ‘TNBC paradox’22.TNBC is character- acteristics of TNBC, its treatment and treatment out- ized by aggressive behavior including high metastatic comes in real-world clinical practice, based on a single potential, higher rates of local and distant disease re- institution experience. 98 Acta Clin Croat, Vol. 59, No. 1, 2020 Ana Tečić Vuger et al. Triple-negative breast cancer Patients and Methods Sample type and sample size required Study design The minimum sample size required was calculated before data collection for the primary objective with We conducted this observational, real-world, sin- the following assumptions: statistical significance level gle-center, retrospective cohort study at the University p<0.05, targeted statistical power of 80%, eight prog- Hospital for Tumors, Sestre milosrdnice University nostic factors (age, menopausal status, comorbidities, Hospital Centre, Zagreb, Croatia, with 5-year follow- histologic type, tumor size, number of positive lymph up, on a consecutive sample of all women diagnosed nodes and grade, all measured at the time of diagno- with and treated for early TNBC from January 1, 2009 sis), and minimum partial coefficient of determination to December 31, 2012. The study protocol was ap- considered clinically relevant R2 ≥0.10. Under these as- proved by the
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