Alexios Matikas

Background Compared to middle-aged women, older women have a higher risk of breast cancer death. Whether the increased risk of breast cancer death is present in all subgroups of older adults with breast cancer, or negligible in the subgroups receiving adequate surgical and oncological treatment, has been debated. We studied long-term prognosis by age and subtype, adjusting for stage, treatment, socioeconomic status and comorbidity, clarifying which subgroups of older patients that are at increased risk of breast cancer death. Methods In a nation-wide cohort of 45,949 women aged ≥60 years at diagnosis of breast cancer 1997-2014, we estimated crude probabilities of breast cancer death and from other causes using competing risk methods. Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) with 95% confidence intervals (CI. Results In this large population-based …

Background Breast surgery in cases of de novo metastatic breast cancer (MBC) is associated with improved outcomes in retrospective studies, although the results of randomized controlled trials (RCTs) are conflicting. We aimed to investigate whether surgery in this context prolongs patient survival. Methods We performed a systematic review of the literature to identify RCTs comparing surgery of primary breast cancer to no surgery in patients with de novo MBC. Cochrane Library, Embase, Medline (OVID), and Web of Science were searched with latest update in July 2023, while conference proceedings were manually searched. Data concerning patient and tumor characteristics, as well as outcomes, were extracted. A meta-analysis with random effects models was performed considering heterogeneity between trials. Results Overall, 3255 entries were identified and 5 RCTs fulfilled all inclusion criteria, which had enrolled 1381 patients. The overall estimation in the intention-to-treat population showed no benefit for patients who had surgical excision of the primary breast tumor (HR = 0.93; 95% CI, 0.76-1.14). No subgroups in terms of receptor status or patterns of metastasis seemed to benefit from surgery, except for younger/premenopausal patients (HR = 0.74, 95% CI, 0.58-0.94). Breast surgery was associated with improved local progression-free survival (HR = 0.37, 95% CI, 0.19-0.74). Conclusion Surgery of the primary tumor in patients with de novo MBC does not prolong survival, except possibly in younger/premenopausal patients. Breast surgery should be offered within the context of well-designed clinical trials examining the issue.

BackgroundThe clinical utility of gene signatures in older breast cancer patients remains unclear. We aimed to determine signature prognostic capacity in this patient subgroup.MethodsResearch versions of the genomic grade index (GGI), 70-gene, recurrence score (RS), cell cycle score (CCS), PAM50 risk-of-recurrence proliferation (ROR-P), and PAM50 signatures were applied to 39 breast cancer datasets (N = 9583). After filtering on age ≥ 70 years, and the presence of estrogen receptor (ER) and survival data, 871 patients remained. Signature prognostic capacity was tested in all (n = 871), ER-positive/lymph node-positive (ER + /LN + , n = 335) and ER-positive/lymph node-negative (ER + /LN−, n = 374) patients using Kaplan–Meier and multivariable Cox-proportional hazard (PH) modelling.ResultsAll signatures were statistically significant in Kaplan–Meier analysis of all patients (Log-rank P …

Background: Oncofertility counseling in BRCA carriers has unique challenges due to a possible negative impact of germline pathogenic/likely pathogenic variants (PVs) on reproductive potential and the indication to undergo risk-reducing bilateral salpingo-oophorectomy. While previous studies demonstrated the safety of pregnancy in women with prior breast cancer (BC) history, limited evidence exists in BRCA carriers specifically. We report the results of the largest study to date investigating likelihood of pregnancy after BC, reproductive and disease outcomes specifically in BRCA carriers. Methods: This was an international, multicenter, hospital-based, retrospective cohort study including young BRCA carriers with history of BC (NCT03673306). Eligible patients were women harboring germline PVs in BRCA1 and/or BRCA2 and diagnosed with stage I-III invasive BC at the age of ≤ 40 years between January …

Background: The PREDIX HER2 trial (n= 202) compared neoadjuvant docetaxel, trastuzumab, and pertuzumab (DHP) vs. trastuzumab emtansine (T-DM1) in HER2-positive breast cancer, resulting in similar pathologic complete response (pCR) rates.Methods: Fresh-frozen pre-treatment biopsies were used for RNA, DNA and protein extraction and subsequent RNA-sequencing (n= 187), shallow whole-genome sequencing (n= 179), exome sequencing (n= 190) and mass spectrometry-based proteomics (n= 170). Tumor intrinsic molecular features and microenvironment components were quantified and associated with pCR in each arm using logistic regression. Predictive value was evaluated by adding the interaction term between biomarker and arm. In addition, a machine learning analysis was conducted with a treatment-stratified ensemble of 3 classifiers (Logistic Regression, Random Forest and SVM) trained …

Breast cancer is the most common malignancy diagnosed during or directly after pregnancy. Differences in pathogenesis and prognosis identify two distinct patient groups, those with breast cancer during pregnancy and those with postpartum breast cancer which, for reasons not completely understood, is associated with worse outcomes. Compared with breast cancer in the non‐pregnant patient, several limitations in terms of both local and systemic therapy are applied to limit fetal harm. Treatment is nevertheless delivered with curative intent, therefore avoiding harmful delays in therapy initiation, unnecessary therapy de‐escalation or chemotherapy dose modifications is strongly recommended. In this short commentary, we briefly review current evidence and treatment guidelines and provide recommendations for optimal oncologic management of pregnancy‐related breast cancer.

PurposeAn increased incidence of hypothyroidism among breast cancer survivors has been observed in earlier studies. The impact of the postoperative treatment modalities and their potential interplay on hypothyroidism development needs to be studied.MethodsWe conducted a population- and registry-based study using the Breast Cancer Data Base Sweden (BCBaSe) including females diagnosed with breast cancer between 2006 and 2012. In total, 21,268 female patients diagnosed with early breast cancer between 2006 and 2012, with no previous prescription of thyroid hormones and no malignant diagnosis during the last ten years before breast cancer diagnosis, were included in the final analysis.ResultsDuring the follow-up (median follow-up time 7.9 years), 1212 patients (5.7%) developed hypothyroidism at a median time of 3.45 years from the index date. No association of the systemic oncological …

PurposeGene expression profiles are used for decision making in the adjuvant setting of hormone receptor positive, HER2 negative (HR+/HER2-) breast cancer. Previous studies have reported algorithms to optimize the use of RS/Oncotype Dx but no such efforts have focused on ROR/Prosigna. We sought to improve pe-selection of patients before testing using machine learning.MethodsPostmenopausal women with resected HR+/HER2-node negative breast cancer tested with ROR/Prosigna in four Swedish regions were included (n= 348). We used the ROR/Prosigna assessment results to compare the performance of four risk classifications in terms of over-and undertreatment. We developed and validated a machine learning model that comprised simple prognostic factors (size, progesterone receptor expression, grade and Ki67) for prediction of ROR/Prosigna outcome.ResultsAdherence to guidelines reached 66.3%, with non-tested patients being older and having more comorbidities (p< 0.001). Previous risk classifications led to excessive undertreatments (CTS5: 21.8%, MINDACT/TailorX risk definitions: 28.1%) or large intermediate groups that would need to be tested with gene expression profiling (Ki67 cut-offs according to Plan B: 86.5%). The model achieved AUC under ROC for predicting ROR/Prosigna result of 0.77 in the training and 0.83 in the validation cohort. By setting and validating upper and lower cut-offs in the model, we could improve correct risk stratification and decrease the proportion of patients needing testing with ROR/Prosigna compared to current management.ConclusionWe show the feasibility of machine learning …

BackgroundThymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in human epidermal growth factor 2 (HER2)-negative early and metastatic breast cancer (BC). However, the prognostic and predictive value of serial TK1 activity in HER2-positive BC remains unknown.MethodsIn the PREDIX HER2 trial, 197 HER2-positive BC patients were randomized to neoadjuvant trastuzumab, pertuzumab, and docetaxel (DPH) or trastuzumab emtansine (T-DM1), followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum samples were prospectively collected from all participants at multiple timepoints: at baseline, after cycle 1, 2, 4, and 6, at end of adjuvant therapy, annually for a total period of 5 years and/or at the time of recurrence. The associations of sTK1 activity with baseline …

The treatment landscape of solid tumors has changed markedly in the last years. Molecularly targeted treatments and immunotherapies have been implemented and have, in many cancers, lowered the risk of relapse and prolonged survival. Patients with tumors harboring specific targetable molecular alterations or mutations are often of a younger age, and hence future fertility and family building can be important concerns in this group. However, there are great uncertainties regarding the effect of the new drugs on reproductive functions, including fertility, pregnancy and lactation and how young patients with cancers, both women and men should be advised. The goal with this review is to gather the current knowledge regarding oncofertility and the different novel therapies, including immune checkpoint inhibitors, antibody-drug conjugates, small molecules and monoclonal antibody targeted therapies. The specific …

ImportanceYoung women with breast cancer who have germline pathogenic variants inBRCA1orBRCA2face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regardingBRCAcarriers.ObjectiveTo investigate cumulative incidence of pregnancy and disease-free survival in young women who areBRCAcarriers.Design, Setting, and ParticipantsInternational, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants inBRCA1and/orBRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023.ExposurePregnancy after breast cancer.Main Outcomes and Measures …

Background: The PREDIX HER2 trial, compared six courses of docetaxel, trastuzumab, and pertuzumab (DTP) vs. trastuzumab emtansine (T-DM1) as neoadjuvant treatment for HER2-positive breast cancer (BC). Similar rates of pathologic complete response (pCR) were seen. Methods: Clinicopathological, shallow whole-genome sequencing (CUTseq, n=176), whole exome sequencing (WES, n=192), and RNA-sequencing (RNA-seq, n=187) data were generated using fresh-frozen baseline core biopsies. Potential tumor intrinsic resistance factors and microenvironment components were quantified by multi-omics analysis, including BC-specific somatic mutations and copy number alterations (CNA), COSMIC mutational signatures, CNA-based chromosomal instability signatures (CIN), subclone percentage, PAM50 subtype, GGI/PIK3CA score, HER2DX score, immune profiles (Danaher signature score, TIDE score …

Background: The PREDIX HER2 trial compared standard neoadjuvant therapy with 6 cycles of docetaxel, trastuzumab, and pertuzumab (DTP), versus 6 cycles of trastuzumab emtansine (T-DM1) in 197 patients with HER2-positive breast cancer. There was no difference in pathologic complete response (pCR) rate and event-free survival (EFS) between the two treatments (Hatschek, JAMA Oncology 2021). Here we systematically evaluate the prognostic and predictive molecular biomarkers during neoadjuvant HER2-targeting therapy. Methods: Longitudinal fresh-frozen tissue biopsies (pretreatment (n=194) and after 2 cycles (n=167)) and surgical specimens (n=126) were collected and sequenced by RNA-sequencing (RNA-seq). Differential gene expression (DGE) analyses were conducted using zero-inflated negative binomial mixed model, and P-values were adjusted by the Benjamini-Hochberg method …

Artificial intelligence (AI) is becoming increasingly used in radiology over the past years due to the astonishing variety of tools and plugins intended for image analysis and modeling. Specifically, the use of radiomics, describing the development of imaging signatures from a number of handcrafted imaging features, is gaining ground since it has shown great promise toward accelerating personalized diagnosis and therapy in healthcare. A de novo synthesis of a radiomics analysis pipeline can be technically complex and requires a carefully designed step-by-step analysis infrastructure, most frequently conducted by AI experts. However, the end result and the benefit of such an analysis can be accessible to an extended number of professionals through the use of user-friendly software tools that do not demand explicit knowledge of the theoretical framework. In view of the above, the aim of this chapter is not only to …

Purpose PREDIX HER2 is a randomized Phase II trial that compared neoadjuvant docetaxel, trastuzumab, and pertuzumab (THP) with trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Rates of pathologic complete response (pCR) did not differ between the two groups. Here, we present the survival outcomes from PREDIX HER2 and investigate metabolic response and tumor-infiltrating lymphocytes (TIL) as prognostic factors. Patients and Methods In total, 202 patients with HER2-positive breast cancer were enrolled and 197 patients received six cycles of either THP or T-DM1. Secondary endpoints included event-free survival (EFS), recurrence-free survival (RFS), and overall survival (OS). Assessment with PET/CT was performed at baseline, after two and six treatment cycles. TILs were assessed manually at baseline biopsies, while image-based evaluation of …

Early, non-metastatic breast cancer (BC) is treated with a combination of surgery, radiotherapy and systemic therapies, such as cytotoxic chemotherapy and targeted drugs, including endocrine therapy and HER2-targeting antibodies for ER-positive and HER2-positive BC, respectively. Although systemic therapies were initially developed post-operatively (adjuvant), their use has later expanded to the primary, pre-operative setting (neoadjuvant or primary systemic therapy—PST).Initial interest in PST focused on timely eradication of micrometastatic disease, in vivo testing of chemosensitivity and the possibility of down-staging in order to increase resectability of initially inoperable tumors and to employ more conservative surgical approaches. Despite the obvious theoretical advantages and opportunities for improving outcomes, effectively using cytotoxic drugs and facilitating surgery, the use of PST initially met some …

BackgroundThe recommended preoperative approach for HER2-positive breast cancer is unclear. We aimed to investigate: i) what is the optimal neoadjuvant regimen and ii) whether anthracyclines could be excluded.MethodsA systematic literature search in Medline, Embase and Web of Science databases was performed. Studies had to satisfy the following criteria: i) randomised controlled trials (RCTs), ii) enrolled patients treated preoperatively for HER2-positive BC, iii) at least one treatment group received an anti-HER2 agent, iv) available information of any efficacy endpoint and v) published in English. A network meta-analysis with a frequentist framework using random-effects model was used to pool direct and indirect evidence. Pathologic complete response (pCR), event-free survival (EFS) and overall survival (OS) were the efficacy endpoints of interest and selected safety endpoints were also analysed …

BackgroundThe advent of targeted therapies signaled novel avenues for more optimal oncological outcomes. Antibody-drug conjugates (ADCs) have risen as a cornerstone of the ever-expanding targeted therapy era. The purpose of this systematic review is to delineate the rapidly evolving clinical landscape of ADCs for solid tumors.MethodsA literature search was performed in Medline, Embase and Cochrane databases for phase II and III clinical trials. Outcomes of interest were the objective response rate, overall survival, progression-free survival and adverse events.ResultsA total of 92 clinical trials (76 phase II and 16 phase III) evaluated the efficacy and safety of ADCs for a plethora of solid tumors. Out of the 30 investigated ADCs, 8 have received approval by regulatory organizations for solid tumors. Currently, 52 phase III clinical trials for ADCs are ongoing.ConclusionADCs have shown promising results for …

Treatment with immune checkpoint inhibitors (ICI) has revolutionized cancer management for multiple tumor types, including breast cancer. However, not all patients respond to ICI, and unraveling the determinants and mechanisms of response still remains an unmet need. A recent study has uncovered the critical role of eosinophils in mediating immunotherapy effect in breast cancer, mainly by stimulating the activation of CD8+ T‐cells. Furthermore, the intratumoral eosinophil recruitment was directed by CD4+ T cells and the interleukins IL‐5 and IL‐33, thus providing the rationale for targeting eosinophils to enhance ICI response.

Young oncologists around the globe face many challenges when it comes to their career and professional development. Aspects such as time management, work-life balance, career progression, and educational opportunities are only some of them. Professional societies have identified these challenges in this professional group and designed programs to tackle them specifically. The importance of this strategy cannot be overstated, as young oncologists, defined by most societies as oncologists under 40 years of age, compose almost 50% of the oncology workforce. On the other hand, recent surveys have shown that many young oncologists are considering alternative career paths due to burnout issues aggravated by the COVID-19 pandemic, on top of all other challenges. The virtual setting that has been forcedly introduced into our professional life has shortened distances between professionals and might have …