High Parity Predicts Poor Outcomes in Patients With Luminal B-Like (HER2 Negative) Early Breast Cancer : A Prospective Finnish Single-Center Study

While breast cancer prognoses are generally good, different molecular subtypes are known to have varying outcomes. Previous studies using breast cancer registries have suggested that high parity may be an adverse prognostic factor in luminal breast cancer, but breast cancer subtype definitions have varied and there have been few prospective studies. We therefore collected prospective data from patients diagnosed with early breast cancer at a single institution and followed them for a median of 8.5 years. All patients (N= 594) were treated according to Finnish national guidelines using modern treatment modalities in a Finnish university hospital. Clinicopathological surrogates of the intrinsic breast cancer subtypes were updated to match European Society for Medical Oncology 2015 Early Breast Cancer Clinical Practice Guidelines. The overall 10-year breast cancer-specific survival (BCSS) was 91.4%, with the longest 10-year BCSS observed in luminal A-like cancers (97.9%) and the worst in luminal B-like (HER2 positive) cancers (80.6%). Parity of >= 5 deliveries was also associated with poor BCSS (univariateP= 0.0020). However, when the subtypes were assessed separately in a multivariate analysis that included tumor size and nodal status, high parity remained significant only in luminal B-like (HER2 negative) cancers (HR = 2.63; 95% confidence interval = 1.04-6.62;P= 0.040). Our results suggest excellent overall 10-year BCSS but indicate that high parity is an adverse prognostic factor in luminal B-like (HER2 negative) breast cancers.Peer reviewe

Primary neuroendocrine breast carcinomas are associated with poor local control despite favourable biological profile : a retrospective clinical study

Background: Breast carcinomas with neuroendocrine features (NEBC) are a very rare entity of mammary neoplasms, WHO classification of which has recently been revised. There are very limited data available about the clinical behaviour and treatment options of NEBC. Methods: We collected retrospectively patients with NEBC from Oulu and Helsinki University Hospitals in 2007-2015. There were 43 NEBC cases during the period. Results: The incidence of NEBC from all breast cancers varied from 0.1% in Helsinki to 1.3% in Oulu. The mean tumor size was 2.2 cm and 23 patients (55.8%) had no lymph node metastases when diagnosed. In total, 4 patients (9.3%) had distant metastases at the time of diagnosis. High estrogen receptor (ER) expression was observed in 41 (97.7%) patients. When non-metastatic NEBC were compared to a prospective set of ductal carcinomas (n = 506), NEBC were more often HER2 negative (p = 0.046), ER positive (p = 0.0062) and the NEBC patients were older (p <0.0005) than patients with ductal carcinomas. Plasma chromogranin A correlated only to higher age at diagnosis (p = 0. 0028). Relapse-free survival (p = 0.0013), disease-free survival (p = 0.024) and overall survival (p = 0.0028) favoured ductal carcinomas compared to NEBC, while no difference was observed in distant disease-free survival or in breast cancer-specific survival. Conclusions: There is remarkable variation in the incidence of NEBC in Finland, which is likely to be explained by differences in the use of neuroendocrine marker immunostainings. Poor local control and worse overall survival may be linked to the more aggressive biology of the disease, despite its association with apparently indolent prognostic factors.Peer reviewe

How breast cancer recurrences are found : a real-world, prospective cohort study

Background: There is very limited data available on how most breast cancer recurrences, either distant metastases or locoregional recurrences (LRR), are actually discovered in routine clinical practice. Patients and methods: From a prospective cohort of 621 women diagnosed and treated for early invasive breast cancer between 2003 and 2013, we analysed the patients who were later diagnosed with distant metastases (n = 61) and the patients who had locoregional recurrences (LRR; n = 34). The patients had routine control visits for up to 10 years from initial diagnosis, with annual clinical visits, mammography, blood count, plasma creatinine and liver function tests. Results: Most distant metastases (n = 38, 62%) were found when a patient contacted health care services because of a symptom; only ten (16%) were detected at pre-planned control visits. The most common first sign or symptom of metastasis was pain (n = 23, 38%). Pain as the first indicator of metastasis indicated a lower survival in metastatic disease (hazard ratio 4.40; 95% confidence interval 1.77–10.94; p = 0.001). How relapse was detected or whether patient was symptomatic did not affect overall survival (OS) of patients with distant metastases. LRRs were mostly found at pre-planned control visits (n = 14, 41%). Abnormalities in routine laboratory tests did not lead to any detection of recurrence. Discussion: In this prospective, contemporary, real-world study, the vast majority of both distant metastases and LRRs were detected outside the pre-planned control visits. These results highlight the importance of finding ways to lower the threshold for contacting the surveillance unit, rather than frequent routine controls.acceptedVersionPeer reviewe

Comparison of the mutational profiles of neuroendocrine breast tumours, invasive ductal carcinomas and pancreatic neuroendocrine carcinomas

The pathophysiology and the optimal treatment of breast neuroendocrine tumours (NETs) are unknown. We compared the mutational profiles of breast NETs (n = 53) with those of 724 publicly available invasive ductal carcinoma (IDC) and 98 pancreatic NET (PNET) cases. The only significantly different pathogenetic or unknown variant rate between breast NETs and IDCs was detected in the TP53 (11.3% in breast NETs and 41% in IDCs, adjusted p value 0.027) and ADCK2 (9.4% in breast NETs vs. 0.28% in IDCs, adjusted p value 0.045) genes. Between breast NETs and PNETs, different pathogenetic or unknown variant frequencies were detected in 30 genes. For example, MEN1 was mutated in only 6% of breast NETs and 37% in PNETs (adjusted p value 0.00050), and GATA3 pathogenetic or unknown variants were only found in 17.0% of breast NETs and 0% in PNETs (adjusted p value 0.0010). The most commonly affected oncogenic pathways in the breast NET cases were PI3K/Akt/mTOR, NOTCH and RTK-RAS pathways. Breast NETs had typically clock-like mutational signatures and signatures associated with defective DNA mismatch repair in their mutational landscape. Our results suggest that the breast NET mutational profile more closely resembles that of IDCs than that of PNETs. These results also revealed several potentially druggable targets, such as MMRd, in breast NETs. In conclusion, breast NETs are indeed a separate breast cancer entity, but their optimal treatment remains to be elucidated.Peer reviewe

Evaluation of DNA-based eye color prediction tool IrisPlex in Finnish population

Externally visual characteristics such as hair, skin and eye pigmentation or clothes have always been used for suspect identification. Also the opposite - to link unknown body parts or only DNA to a person - is recently tried to be introduced into forensics. I am testing the feasibility of one such method, IrisPlex, in Finnish population. The IrisPlex method was first published by Walsh et al. (2011). IrisPlex uses six single nucleotide polymorphisms (SNPs) in different genes found to affect the most in eye color variation. SNPs were detected from DNA sample by single base extension method, SNaPshot. Based on this information from DNA of a participant, the prediction of the most probable eye color was generated with a multinomial regression model. Also the genotypic information in the six loci and differences between Eastern and Western Finns were studied. In addition, this study supplements the knowledge of eye color frequencies across Europe. This study revealed that IrisPlex does work appropriately in Finns when detecting the blue and brown eye colors: 80% of the study participants' eye colors were predicted correctly. The biggest weakness of IrisPlex is its incapability to predict the intermediately colored eyes. Prediction probability differences between genders were not detected. In the study population 60% of the participants had blue eyes (28 individuals), 13% had brown eyes (6 individuals) and 28% (13 individuals) intermediately colored eyes. When the eyes were divided into two categories, the portion of blue-eyed participants was 77% (36 individuals) and brown-eyed participants 23% (11 individuals). These results are consistent with previous studies and update the color frequencies. Genetic segmentation of Finnish people in Eastern and Western Finland has been established in multiple studies. In addition to previous ones, this study is consistent with the genetic segmentation theory between Eastern and Western Finland. Darker eyes were observed slightly more frequently in participants with north-east heritage than in participants with south-west heritage. However, the studied populations were small and the result was insignificant. Additionally, the studied population sample represents the narrow gene pool of the Finns; almost half of the participants, 42%, reported all or 3 of their grandparents to have been born in the same village. The allele and genotype frequencies were also studied and compared to another study, in which these SNPs have been studied in the Finns and the results were consistent. Altogether, this study strengthens the evidence that IrisPlex has potential in forensic, archeological and anthropological applications even in genetically isolated populations as the Finns. This study supports the IrisPlex method to be further developed and especially addresses the need for better sensitivity for intermediate eye color

New prognostic markers and prognosis in various breast cancer subtypes

Abstract Breast cancer is the most common cancer in Finnish women and nearly 5 000 are diagnosed yearly. Surgical resection of the tumour is the primary treatment for localized breast cancer, but other treatment modalities such as chemotherapy, radiotherapy, endocrine therapy, antibodies or antibody conjugates, are also used, mainly in the adjuvant setting. The average prognosis for breast cancer is very good, but metastatic breast cancer is still incurable. Parity is suggested to play a role in the development of breast cancer, but how it does is still controversial. Neuroendocrine breast cancer is a rare sub-type, involving less than 1% of the breast cancers. Usually, neuroendocrine cancers originate from the gastrointestinal tract or lung, so it is important to identify the extra-mammary origin of a tumour. The neuroendocrine cancers of the gastrointestinal tract are characterized by the expression of, for example, the somatostatin receptor and p27 protein. Oxidative compounds are produced in normal cellular metabolism. The compounds are broken down by antioxidants such as thioredoxin and the process is regulated by Keap1 protein. Oxidative compounds are harmful because they can damage the DNA and thus predispose to the development of cancer. In this PhD thesis antioxidative enzymes, already known to be neuroendocrine markers, and parity were studied to identify any association with the prognosis of breast cancer. The study shows that, overall, breast cancer has a very good prognosis: 91.4% of the patients are alive 10 years after diagnosis. Neuroendocrine breast cancer, on the other hand, is shown to be more aggressive than was assumed, and the patients were, on average, older. The survival of women with ≥ 5 deliveries was poorer, but only in luminal B-like cancers. Both the antioxidative enzyme and neuroendocrine marker expression were favourable in terms of survival. Especially somatostatin receptor and p27 protein expression associated with better survival.Tiivistelmä Rintasyöpä on naisten yleisin syöpä Suomessa — diagnoosin saa vuosittain noin 5 000 suomalaista. Ensisijainen hoito paikallisessa rintasyövässä on kasvaimen kirurginen poisto. Rintasyöpää hoidetaan myös solunsalpaajilla, sädehoidolla, hormonaalisilla lääkehoidoilla sekä vasta-ainehoidoilla. Rintasyöpä on hyväennusteinen tauti, mutta metastasoinut rintasyöpä on yhä parantumaton sairaus. Synnytysten määrällä on arveltu olevan vaikutusta rintasyövän kehitykseen, mutta tutkimustieto aiheesta on ristiriitaista. Neuroendokriininen rintasyöpä on harvinainen alatyyppi, joka kattaa alle 1 % rintasyövistä. Neuroendokriininen syöpä esiintyy tavallisesti suolistossa tai keuhkoissa, joten diagnosointivaiheessa onkin selvitettävä, että kyseessä on rinnasta alkunsa saanut syöpä. Neuroendokriinisista kasvaimista tiedetään, että ne ilmentävät esimerkiksi somatostatiinireseptoreja ja p27-proteiineja. Ihmisen solujen normaalissa aineenvaihdunnassa syntyy hapettavia yhdisteitä, joita antioksidantti tioredoksiini hajottaa ja joiden säätelyyn osallistuu esim. Keap1-entsyymi. Hapettavat yhdisteet ovat soluille haitallisia, sillä ne vahingoittavat solun DNA:ta ja voivat altistaa syövän kehittymiselle. Tässä väitöstutkimuksessa selvitettiin, vaikuttavatko antioksidatiivisten entsyymien, suoliston neuroendokriinimerkkiproteiinien esiintyminen tai synnytysten määrä rintasyövän ennusteeseen. Tutkimuksen perusteella rintasyöpä on yleensä hyväennusteinen tauti: 91,4 % on elossa 10 vuoden päästä diagnoosista. Neuroendokriiniset rintasyövät paljastuivat odotettua aggressiivisemmiksi ja sairastuneet olivat keskimäärin iäkkäämpiä naisia. Vähintään viisi kertaa synnyttäneiden selviytyminen rintasyövästä oli muita harvinaisempaa, kun kyseessä oli luminaalinen B-tyypin syöpä. Sekä antioksidatiivisten entsyymien että neuroendokriinimerkkiaineiden esiintyminen ennusti parempaa syöpäselviytymistä. Myös somatostatiinireseptori ja p27-proteiini ennustivat parempaa syöpäselviytymistä

Prognostic factors in metastatic breast cancer : a prospective single-centre cohort study in a Finnish University Hospital

Objectives Although novel early breast cancer prognostic factors are being continuously discovered, only rare factors predicting survival in metastatic breast cancer have been validated. The prognostic role of early breast cancer prognostic factors in metastatic disease also remains mostly unclear. Design and setting Prospective cohort study in a Finnish University Hospital. Participants and outcomes 594 women with early breast cancer were originally followed. Sixty-one of these patients developed distant metastases during the follow-up, and their primary breast cancer properties, such as tumour size, nodal status, oestrogen receptor (ER) and progesterone receptor expression, grade, proliferation rate, histopathological subtype and breast cancer subtype were analysed as potential prognostic factors for metastatic disease. Results In multivariate analysis, the presence of lymph node metastases at the time of early breast cancer surgery (HR, 2.17; 95% CI, 1.09-4.31; p=0.027) and ER status (negative vs positive, HR, 2.16; 95% CI, 1.14-4.10; p=0.018) were significant predictors of survival in metastatic disease. Conclusions These results confirm ER status as a primary prognostic factor in metastatic breast cancer. Furthermore, it also suggests that the presence of initial lymph node metastases could serve as a prognostic factor in recurrent breast cancer.Peer reviewe

Real-world, single-centre prospective data of age at breast cancer onset : focus on survival and reproductive history

Objectives Being either young or old at the time of breast cancer diagnosis has been suggested as an indicator of a poor prognosis. We studied the effect of age at breast cancer onset in relation to survival, focusing in particular on biological subtypes and reproductive anamnesis. Design, setting and participants Patients with early breast cancer (n=594) treated in a Finnish University Hospital during 2003-2013 were prospectively collected and followed in median 102 months. Results Patients with luminal A-like breast cancer were older than the patients with luminal B-like (HER2-positive) (p=0.045) or patients with the HER2-positive (non-luminal) subtype (p=0.029). Patients >= 70 years received substantially less adjuvant chemotherapy (p=1.5x10(-9)) and radiotherapy (p=5.9x10(-7)) than younger women. Nevertheless, the estimated 10-year breast cancer-specific rates of survival were 84.2%, 92.9% and 87.0% in age groups = 70 years, respectively, with no statistical difference (p=0.115). Survival rates were also comparable between the three age groups when assessed separately in different biological subtypes, and for patients with metastatic breast cancer there was similarly no difference between the age groups. Later menarche (p=5.7x10(-8)) and high parity (p=0.000078) correlated with increased age at breast cancer diagnosis, but, according to the patients' oestrogen receptor (ER) status, only among ER-positive patients. Conclusions Despite the suggested undertreatment of older patients, we report excellent long-term outcomes in all age groups in this prospective cohort. Later endogenous endocrine exposure may cause delay in breast cancer onset, but the exact biology behind this phenomenon is so far unclear.Peer reviewe

The role of redox-regulating enzymes in inoperable breast cancers treated with neoadjuvant chemotherapy

Abstract Although validated predictive factors for breast cancer chemoresistance are scarce, there is emerging evidence that the induction of certain redox-regulating enzymes may contribute to a poor chemotherapy effect. We investigated the possible association between chemoresistance and cellular redox state regulation in patients undergoing neoadjuvant chemotherapy (NACT) for breast cancer. In total, 53 women with primarily inoperable or inflammatory breast cancer who were treated with NACT were included in the study. Pre-NACT core needle biopsies and postoperative tumor samples were immunohistochemically stained for nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), thioredoxin (Trx), and peroxiredoxin I (Prx I). The expression of all studied markers increased during NACT. Higher pre-NACT nuclear Prx I expression predicted smaller size of a resected tumor (p = 0 00052; r = −0 550), and higher pre-NACT cytoplasmic Prx I expression predicted a lower amount of evacuated nodal metastasis (p = 0 0024; r = −0 472). Pre-NACT nuclear Trx expression and pre-NACT nuclear Keap1 expression had only a minor prognostic significance as separate factors, but when they were combined, low expression for both antibodies before NACT predicted dismal disease-free survival (log-rank p = 0 0030). Our results suggest that redox-regulating enzymes may serve as potential prognostic factors in primarily inoperable breast cancer patients