Hypoxia in solid tumors: biological responses to hypoxia and implications on therapy and prognosis

Tumor development, promotion and ability to spread depend greatly on tumor microenvironment. Rapid growth accompanied by inadequate angiogenesis is the reason why most solid tumors contain hypoxic regions. Activation of hypoxia signaling pathways stimulates neoangiogenesis, alters tumor metabolism, promotes a more aggressive tumor behavior and significantly affects its responsiveness to therapy. Growing amount of evidence suggest that hypoxia induces transcription of tumor promoting genes leading to increased tumor cell proliferation and metastatic potential. Improved understanding of molecular pathways will enable establishment of useful prognostic and predictive factors, along with more effective treatment options

Hypoxia in solid tumors: biological responses to hypoxia and implications on therapy and prognosis

Tumor development, promotion and ability to spread depend greatly on tumor microenvironment. Rapid growth accompanied by inadequate angiogenesis is the reason why most solid tumors contain hypoxic regions. Activation of hypoxia signaling pathways stimulates neoangiogenesis, alters tumor metabolism, promotes a more aggressive tumor behavior and significantly affects its responsiveness to therapy. Growing amount of evidence suggest that hypoxia induces transcription of tumor promoting genes leading to increased tumor cell proliferation and metastatic potential. Improved understanding of molecular pathways will enable establishment of useful prognostic and predictive factors, along with more effective treatment options

Pneumonitis as a side effect of breast cancer treatment: T-DXd and/or SBRT?

Breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2) is considered to be HER2-positive. The novel HER2- directed antibody drug conjugate, trastuzumab deruxtecan (T-DXd), is formed by covalently joining the monoclonal antibody trastuzumab with the topoisomerase I inhibitor deruxtecan. It exhibits significant anti-tumor activity in previously overtreated patients

A patient with metastasis of breast cancer which was originally described as primary colorectal cancer: case report

Breast cancer metastases can be found in almost all organs in the body - but are most commonly found in the lungs, liver, bones, skin and brain. Metastatic breast cancer often occurs years or decades after initial diagnosis and treatment. In this case report, we will present a 62-year-old patient with metastasis of breast cancer which was originally described as primary colorectal cancer

New primary non-breast malignancies after breast cancer: ten years single institution follow-up

Background and Purpose: Breast cancer is the most common cancer in Croatian women. Due to improved diagnostic and treatment options women with breast cancer now live longer, which increases their risk of developing new primary malignancies. The aim of this study was to establish incidence of new primary non-breast malignancies after breast cancer diagnosis. Material and Methods: In the study cohort that included 215 consecutive patients treated for early breast cancer at University Hospital Center Zagreb, Croatia, 12 patients (5.58%) have developed new primary non-breast malignancy within nearly ten year follow-up. Results: Although the majority of studies found gynecological cancers to be the most common cancer site of new primary non-breast malignancies after breast cancer diagnosis, in our study most patients developed colorectal cancer. Conclusion: This is particularly interesting if you take into account that after breast cancer colorectal cancer is the second most common cancer in Croatian women. In order to stratify the risk for the development of new primary tumors it is necessary to further investigate the interaction of various factors that are thought to influence the evolvement of tumors

NEW PRIMARY MALIGNANCIES AFTER BREAST CANCER DIAGNOSIS: INTERPLAY OF GENETICS, RISK FACTORS AND TREATMENT MODALITIES

Značajan napredak u ranom otkrivanju i kvalitetnije liječenje oboljelih rezultirali su činjenicom da u najrazvijenijim zemljama gotovo 90% žena s dijagnozom raka dojke preživi duže od 5 godina nakon dijagnoze i liječenja. Kod jedne od dvadeset žena oboljelih od raka dojke unutar 10 godina od postavljanja dijagnoze razvit će se novi primarni tumor čije sijelo nije dojka. Mutacije gena BRCA 1 i 2, RAD51C, MMR, p53, CDKN2A te 113insArg povezuju se s povećanim rizikom od razvoja raka dojke i drugih zloćudnih tumora. Čini se da i modalitet liječenja utječe na povećanje rizika od razvoja novoga zloćudnog tumora. Tako je nakon radioterapije primijećen povećan rizik za tkiva koja primaju višu dozu zračenja, osobito kod mlađih bolesnica, desetak godina nakon zračenja. Nađena je povećana incidencija leukemije i mijelodisplastičnog sindroma nakon liječenja kemoterapijom u odnosu na opću populaciju, ali smanjen rizik od razvoja zloćudnih tumora ostalih sijela. Odranije poznat povećan rizik od razvoja raka endometrija nakon hormonske terapije tamoksifenom potvrđen je i u novijim studijama. Mehanizam nastanka novih primarnih zloćudnih tumora nije potpuno razjašnjen. Koliki udio u tome imaju zajednički nasljedni čimbenici, mogući zajednički okolišni rizični čimbenici ili neželjene nuspojave specifičnog onkološkog liječenja tek se treba otkriti.Significant advances in early breast cancer detection and increased quality of care within developed countries resulted in longer than five years survival in almost 90% of women diagnosed and treated for breast cancer. One in twenty women diagnosed with breast cancer will develop a new primary non-breast malignancy within 10 years from initial diagnosis. Mutations in BRCA 1 i 2, RAD51C, MMR, p53, CDKN2A and 113insArg genes are linked with increased risk of breast cancer and other cancer sites. It seems that treatment modalities also play significant role in development of new primary malignancies. Tissues that receive higher doses of radiation during radiotherapy of breast cancer are under increased risk of developing new primary tumor, especially in younger women, ten years after the treatment. Chemotherapy may cause higher incidence of leukemia and myelodysplastic syndrome but lower overall risk for development of other malignancies. Connection between tamoxifen therapy and increased risk of endometrial cancer is well known and confirmed also in recent studies. The true mechanism of cancer development is still unclear. Significance of hereditary factors, possible common environmental risk factors or unwanted side effects of the specific anticancer treatments are yet to be discovered

Prognostička vrijednost topoizomeraze 2-alfa i B-Myb u ranom raku dojke liječenom adjuvantnom kemoterapijom

Breast cancer is the most common malignancy in females. Despite its well-established prognostic factors, our prognostic ability at an individual patient level remains limited. In this study, the immunohistochemical expression of B-Myb and DNA topoisomerase 2-alpha (Topo2a) was analyzed in primary tumors to identify patients with a higher risk of disease recurrence after adjuvant chemotherapy for early invasive breast cancer. We analyzed a cohort of 215 early invasive breast cancer patients having undergone surgery from 2002 to 2003 at the Zagreb University Hospital Centre, including 153 patients treated with adjuvant chemotherapy. All of them were followed-up prospectively for at least ten years according to routine institutional practice. Statistically significant correlations were found between B-Myb and Topo2a expression levels and particular well-established prognostic factors. B-Myb expression was lower in estrogen receptor (ER)-positive tumors (p=0.0773), whereas larger tumors and those with positive lymphovascular invasion displayed a statistically significantly higher B-Myb expression (p=0.0409 and p=0.0196). Higher tumor grade indicated higher Topo2a values (p=0.0102 and p=0.0069). The subgroup with the expression of both proteins above the median value had an almost statistically significantly (p=0.0613) inferior prognosis compared to the rest of the cohort. Study results showed the B-Myb and Topo2a expression to have a prognostic value in breast cancer patients after adjuvant chemotherapy, which should be additionally explored in future studies in a larger patient cohort.Rak dojke je najčešći zloćudni tumor u žena. Unatoč dobro definiranim “tradicionalnim” prognostičkim čimbenicima naša mogućnost prognoze za svaku pojedinu bolesnicu je ograničena. U ovom istraživanju smo analizirali imunohistokemijsku izraženost B-Myb-a i DNA topoizomeraze 2-alfa (Topo2a) u primarnim tumorima kako bi se identificirale bolesnice s većim rizikom povrata bolesti nakon adjuvantne kemoterapije za rani invazivni rak dojke. Analizirana je kohorta od 215 bolesnica s ranim invazivnim karcinomima dojke koje su operirane u Kliničkom bolničkom centru Zagreb od 2002. do 2003. godine, uključujući 153 bolesnice koje su liječene adjuvantnom kemoterapijom. Sve su praćene prospektivno najmanje deset godina prema rutinskoj kliničkoj praksi. Dokazali smo statistički značajne korelacije između razine izraženosti B-Myb i Topo2a te nekih „tradicionalnih” prognostičkih čimbenika. Izraženost B-Myb je bila niža u ER pozitivnim tumorima (p=0,0773), ali su veći tumori, kao i oni s pozitivnom limfovaskularnom invazijom imali statistički značajno veću izraženost proteina B-Myb (p=0,0409 i p =0,0196). Također, pokazali smo da veći gradus tumora ukazuje na višu vrijednost Topo2a (p=0,0102 i p=0,0069). Pokazali smo da podskupina bolesnica s izraženošću oba proteina iznad srednje vrijednosti ima lošiji ishod bolesti u odnosu na ostatak skupine, ali rezultat je blizu granice statističke značajnosti (p=0,0613). Naše istraživanje je pokazalo prognostičku vrijednost kombinacije prekomjerne imunohistokemijske izraženosti B-Myb i Topo2a u bolesnica s rakom dojke nakon adjuvantne kemoterapije, što zaslužuje daljnja istraživanja na većim skupinama bolesnica

RATIONAL USE OF SERUM TUMOUR MARKERS IN DIAGNOSTICS AND TREATMENT OF SOLID TUMOURS

Optimalno zbrinjavanje oboljelih od malignih bolesti, ovisno o vrsti tumora, uključuje i određivanje serumskih tumorskih biljega. Ti su biljezi heterogena skupina molekula čija je koncentracija povišena kod ljudi oboljelih od zloćudnih tumora, ali se u niskim koncentracijama mogu naći i u plazmi zdravih pojedinaca. Povišene koncentracije u plazmi nastaju zbog: promjena u samoj stanici, nekroze stanice te promjene izražaja ili izlučivanja različitih molekula. Kod nekih tumora same tumorske stanice mogu potaknuti druge stanice na lučenje određenih spojeva. U kliničkoj primjeni u ovom je trenutku između ostalih dostupno određivanje nekoliko serumskih tumorskih biljega: CEA, CA 19-9, CA 15-3, CA 125, CYFRA, NSE, PSA, HCG, AFP, LDH i tiroglobulin. Veći broj serumskih tumorskih biljega primjenjuje se eksperimentalno i čeka svoje mjesto u svakodnevnoj kliničkoj primjeni. Smjernice o primjeni tumorskih biljega Nacionalne akademije kliničke biokemije (National Academy of Clinical Biochemistry – NACB) osmišljene su da bi poticale prikladniju upotrebu testova tumorskih biljega od liječnika primarne zaštite, kirurga, onkologa, ginekologa te ostalih specijalista koji se bave bolesni­cima sa solidnim tumorima.Optimal management of patients with solid tumors, depending on the tumour type, includes measurement of serum tumour markers levels. Serum tumour markers are heterogeneous molecules with concentrations elevated in persons with solid tumours, but could also be found in small amounts in plasma of healthy individuals. Elevated plasma concentrations are caused by cell changes, necrosis, changed expression or secretion of different molecules. In some tumour types tumour cells by themselves could stimulate other cells to secrete particular molecules. There are several serum tumour markers in the routine clinical praxis: CEA, CA 19-9, CA15-3, CA 125, CYFRA, NSE, PSA, HCG, AFP, LDH, thyreoglobulin. There are also several serum tumour markers in experimental use, waiting to be included into the routine clinical use. National Academy of Clinical Biochemistry (NACB) practice guidelines for use of tumour markers in clinical practice are designated to encourage more appropriate use of serum tumour marker tests by general medicine practitioners, surgeons, oncologists, and other health care professionals giving care to patients with solid tumours