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Background: Single hormone receptor-positive breast cancers (BCs) display two distinct phenotypes: ER+/PgR– and ER–/PgR+ further stratified by their HER2 status. Their molecular features are not well defined. Our study aimed to identify differentially expressed genes in ER–/PgR+ BCs compared to other phenotypes. Methods: Our cohort comprised 15 ER+/PgR–/HER2–, 11 ER+/PgR–/HER2+, 17 ER–/PgR+/HER2–, 9 ER–/PgR+/HER2+, 5 ER+/PgR+/HER2–, and 5 ER–/PgR–/HER2– invasive BCs collected from 9 Polish and 2 Hungarian centers. The cases were selected from a larger cohort after being matched according to grade, HER2 status, lymph nodes, and distant metastasis status. ER–/PgR+ group was thoroughly validated via immunohistochemistry [Kunc et al. 2022]. The expression of 776 genes was profiled with nCounter® Breast Cancer 360™ Panel in archival formalin-fixed paraffin-embedded tissue samples. A gene was defined as differentially expressed between groups if it met the following criteria: the log2 fold-change in the expression of >1 or ←1 and the p-value < 0.05 (Mann-Whitney U test). Additionally, weighted correlation network analysis (WGCNA) was performed to identify modules of at least 15 highly correlated genes. Subsequently, the association between gene modules and PgR status in ER– subgroup was performed. Identified mRNAs were subjected to functional annotation analysis to determine the top enriched pathways. Results: ER–/PgR+ BCs were characterized by significantly lower expression of ESR1 compared to double-positive (p< 0.001) and ER+/PgR– tumors (p< 0.001), whereas PGR expression was higher compared to ER+/PgR– (p< 0.001), and no significantly different from ER+/PgR+ BCs (p=0.14). Triple-negative BCs had no detectable PGR mRNA. Four genes (MIA, ID4, FOXC1, CDC20) were consistently up-regulated and six genes (FAM214A, MLPH, NFKBIZ, FOS, SLC44A4, SPDEF) were down-regulated in ER–/PgR+/HER2– tumors compared to other HER2– subgroups. Compared to ER+/HER2– BCs, ER–/PgR+/HER2– cases showed up-regulation of 15 genes associated with response to vitamin D, response to ketone, and regulation of transcription, and downregulation of 33 genes involved in response to estrogen, negative regulation of cell population proliferation, regulation of epithelial-mesenchymal transition, and controlled by ESR1 and SUZ12. In WGCNA analysis of the ER– subgroup, PgR status was negatively correlated with 4 gene modules and positively correlated with 1 gene module. In line with differential gene expression analysis, genes negatively correlated with ER–/PgR+ status are regulated by ESR1 and SUZ12 and are involved in the regulation of cell proliferation, extracellular matrix organization, and NOTCH1 signaling. Genes positively correlated with ER–/PgR+ status are regulated by E2F4, FOXM1, SIN3A, NFYB, E2F1, FOS, IRF1, ZMIZ1, and UBTF and participate in cell cycle, regulation of mitosis, and microtubule cytoskeleton regulation. Conclusions: ER–/PgR+ BCs display a distinct mRNA expression profile characterized by the down-regulation of genes controlled by ESR1 and SUZ12. The latter as a part of Polycomb Repressive Complex 2 contributes to chromatin silencing, and some previous studies suggested its role in the regulation of steroid hormone receptors expression. Additionally, ER–/PgR+ BCs overexpress FOXC1 which is linked to more aggressive, high-grade, and treatment-resistant breast cancers. Our data indicate the need to unravel the mechanism of epigenetic regulation of PGR expression, especially its methylation status, in ER–/PgR+ breast cancer. Citation Format: Michał Kunc, Marta Popęda, Michał Bieńkowski, Marcin Braun, Aleksandra Łacko, Barbara Radecka, Joanna Pikiel, Maria Litwiniuk, Katarzyna Pogoda, Magdalena Niemira, Anna Szałkowska, Ewa Iżycka-Świeszewska, Gabor Cserni, Wojciech Biernat, Elżbieta Senkus. Estrogen receptor-negative progesterone receptor-positive breast cancer is a molecularly distinct group characterized by the down-regulation of genes controlled by ESR1 and SUZ12 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-06.

Background The pandemic has accelerated the introduction of more flexible and cost-effective treatment forms. The efficacy of trastuzumab in the intravenous (IV) and SC forms is similar both in early and advanced HER2-positive breast cancer (BC) patients. Compared to IV administration, SC enables reduction of treatment costs and time, and saves equipment and human resources. SC formulation is more convenient for both patients and healthcare providers and may be implemented as a home-based therapy. Recently, systemic anticancer treatment (including chemotherapy) has been increasingly performed at home, improving patient comfort and reducing the burden on the healthcare system. Poland has already implemented home-based treatment with some biologic compounds; however, they have not included trastuzumab in BC patients. Objectives This RWE analysis aims to evaluate the organizational and therapeutic procedures related to the home-based treatment with SC trastuzumab and the attitudes of patients and healthcare providers to this approach. Material and methods The study enrolled early HER2(+) BC patients treated with trastuzumab during the COVID-19 pandemic. Monitoring and treatment duration were consistent with SmPC and reimbursement regulations in Poland. The first 3-6 doses of SC trastuzumab (alone or in combination with CHT) were administered at a cancer center in outpatient and inpatient settings. Subsequent doses were administered at home by 3 qualified breast nurses. Post-injection follow-up was used for educational purposes. Data were analyzed with descriptive statistics. The study was reviewed and approved by the local Bioethics Committee. Results The analysis included 20 patients treated in two comprehensive cancer centers in Poland with a median age of 59 years (range, 36-72 years). Seven patients (35%) were professionally active. The average distance from the place of residence to the cancer center was 24 km (range, 2-65 km). A total of 232 doses were administered (mean 11.6 doses per patient; range 6-14), 133 doses at home and 99 at the cancer center. The overall tolerance of trastuzumab was good and consistent with the known safety profile described in Summary of Product Characteristics. Only 1 patient (5%) discontinued treatment prematurely due to decreased LVEF; another 19 patients completed treatment as planned. For 19 patients (95%), the benefits of SC treatment included time savings, the ability to continue working, and avoiding crowded places and infection risk. 2 patients (10%) considered the nurse’s visit privacy disturbing, while 18 (90%) would recommend home-based drug administration. The average duration of a nurse’s stay at home was 60 minutes (range 30 to 130 minutes). No logistical or technical problems were reported, except for occasional patient lateness. Nurses positively assessed the treatment provided in the nursing office, which was a source of additional knowledge, and experience. The overall impression of home-based therapy was positive for both patients and nurses. The limitation of the study is the declarative nature of the data. Conclusions Home-based treatment with SC trastuzumab should be pursued due to its safety, ease of organization, positive perception by patients and nurses, and reducing healthcare system resources. It can be particularly valuable for disabled patients who have difficulty reaching the hospital and professionally active patients. Specialized, trained nurses can self-sufficiently carry out part of the prolonged trastuzumab treatment, reducing physician involvement. Citation Format: Barbara Radecka, Hudała-Klecha Joanna, Dariusz Sawka, Jolanta Sarga, Bożena Noworolska, Jolanta Sawicka, Elżbieta Duda, Natalia Obruśnik, Patryk Zając. Home-based treatment with subcutaneous (SC) trastuzumab - only a pandemic solution? Real world evidence (RWE) analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-08-13.

The primary function of intracellular heat shock proteins (HSPs) is to protect the cell by suppressing the effects of various stress factors by either refolding misfolded proteins or blocking apoptosis. After neoplastic transformation, cells overexpress HSPs, which act as factors promoting the neoplastic process by stabilizing proteins responsible for carcinogenesis, however, HSPs can be released into the extracellular environment where they act as important modulators of the immune response. In a tumor microenvironment, extracellular HSPs are able to induce a pro- or anti-neoplastic response, using various mechanisms of affecting immune cells, The study of the role of extracellular HSPs in immunomodulation processes is a very important direction in the search for new methods of cancer treatment. This review summarizes reports on the use of HSPs in immunotherapeutic cancer strategies, in particular in cancer vaccine design.

Purpose: P95HER2 (p95) is a truncated form of the HER2, which lacks the trastuzumab-binding site and contains a hyperactive kinase domain. Previously, an optimal clinical cutoff of p95 expression for progression-free survival (PFS) and overall survival (OS) was defined using a quantitative VeraTag assay (Monogram Biosciences) in a training set of trastuzumab-treated metastatic breast cancer (MBC) patients.Experimental Design: In the current study, the predictive value of the p95 VeraTag assay cutoff established in the training set was retrospectively validated for PFS and OS in an independent series of 240 trastuzumab-treated MBC patients from multiple institutions.Results: In the subset of 190 tumors assessed as HER2-total (H2T)-positive using the quantitative HERmark assay (Monogram Biosciences), p95 VeraTag values above the predefined cutoff correlated with shorter PFS (HR = 1.43; P = 0.039) and shorter OS (HR = 1.94; P = 0.0055) where both outcomes were stratified by hormone receptor status and tumor grade. High p95 expression correlated with shorter PFS (HR = 2.41; P = 0.0003) and OS (HR = 2.57; P = 0.0025) in the hormone receptor-positive subgroup of patients (N = 78), but not in the hormone receptor-negative group. In contrast with the quantitative p95 VeraTag measurements, p95 immunohistochemical expression using the same antibody was not significantly correlated with outcomes.Conclusions: The consistency in the p95 VeraTag cutoff across different cohorts of patients with MBC treated with trastuzumab justifies additional studies using blinded analyses in larger series of patients. Clin Cancer Res; 20(10); 2805–13. ©2014 AACR.

PDF file - 1729KB, Supplemental Figure S2. Kaplan-Meier plots for p95 IHC categories within the HER2 overexpressed subset (H2T>13.8 RF/mm2) with p95 IHC 0 in green, 1+ in red, 2+ in black and 3+ in blue. A, Progression free survival. B, Overall survival. C, Progression free survival in the hormone receptor positive subgroup.

PDF file - 474KB, Supplemental Figure S1. Expanded p95 IHC images from Figure 4A.

Oestrogen receptor (ER)-negative (–) progesterone receptor (PgR)-positive (+) is the least common combination of steroid receptor expression observed in breast cancer. There are many controversies regarding the actual existence of ER–/PgR+ phenotype. In the current study, we aimed to perform comprehensive immunohistochemical re-evaluation of ER–/PgR+ breast cancers from multiple institutions. A total of 135 cases of ER–/PgR+ breast cancer were collected from 11 institutions from the period 2006–2020 and subsequently stained with three clinically validated anti-ER antibody clones: SP1 (Roche), 1D5 (Dako), and EP1 (Dako), and two anti-PgR antibody clones: 636 (Dako), and 1E2 (Roche). Clinicopathological characteristics of confirmed and re-categorised cases were analysed. Seventy-six cases retained the original ER–/PgR+ phenotype, including 21 HER2+ and 55 HER2– tumours. Forty-seven cases were ER+ with at least one anti-ER antibody, and 12 cases were re-categorised as double-negatives across all anti-ER and anti-PgR antibodies. No significant differences in survival were observed between groups in the HER2+ category. In the HER2– cohort, confirmed ER–/PgR+, ER+ tumours with discrepant ER staining, and triple negatives had inferior overall survival compared to concordant ER+ cases. Progesterone receptor expression in >20% of cells was identified as an adverse prognostic factor in ER–/PgR+/HER2– breast cancer in a multivariable model adjusted by stage (HR 5.0, 95% CI 1.3–19.2, p=0.019). We performed one of the largest validation studies so far on ER–/PgR+ breast cancer and confirmed the existence of this subgroup. Moreover, we identified high PgR expression as an adverse prognostic factor.

Breast conserving therapy is the primary treatment modality in early-stage breast cancer patients. Despite the development of methods for the intraoperative assessment of tumor margins, 20–30% of patients still require re-resection due to postoperative tumor infiltration at the surgery margins. In recent years, many methods have been developed to reduce the number of re-resections due to margin infiltration. Here we review the current methods together with several more techniques under investigation.

Heat shock proteins (HSPs) are chaperones with highly conservative primary structure, necessary in the processes of protein folding to the most energetically advantageous conformation and maintaining their stability. HSPs perform a number of important functions in various cellular processes and are capable of modulating pathophysiological conditions at the cellular and systemic levels. An example is the high level of HSP expression in neoplastic tissues, which disrupts the apoptosis of transformed cells and promotes the processes of proliferation, invasion, and metastasis. In addition, an increasing amount of information is appearing about the participation of HSPs in the formation of multidrug resistance. This paper provides a review of the current state of research on the fundamental importance as well as the diagnostic and prognostic role of various classes of HSP in cancer treatment. It presents the prospects for using HSPs as biological markers of disease progression and targets in various cancer treatment strategies. However, the need for additional research is quite high. Only numerous joint efforts of research groups will allow the effective use of HSPs as a tool to combat cancer.

Pancreatic cancer is one of the most common malignancies with poor prognosis and high mortality. Advanced-stage disease at diagnosis and the dominant clinical symptoms significantly deteriorate the quality of life. The paper presents an analysis of the results of quality of life studies in patients with locally advanced and metastatic pancreatic cancer, as well as the relationship between therapeutic decisions and quality of life indicators. It has been shown that the initial assessment of life quality can have prognostic value. Appropriate symptomatic treatment of patients with advanced pancreatic cancer improves the quality of life, increases the compliance and prolongs survival. The assessment of the quality of life in patients with advanced pancreatic cancer has multivariable significance, which is not limited only to improving the quality of life.

Breast cancer is the most commonly diagnosed malignancy in women in Poland. Rare, unusual forms of breast cancer remain a diagnostic problem. The incidence of ectopic breast glandular tissue in the general population varies between 0.4 and 6%. The same abnormalities and diseases as in the anatomical mammary gland may develop in this tissue. Breast cancer may develop as well. We present the case of a 36-year-old woman, who went to the doctor because of a nodule in the right armpit presented for 2 years. The patient was referred to a surgeon with suspicion of an epidermal cyst. The lesion was surgically removed and in the histopathological examination, the diagnose was: invasive breast cancer in ectopic glandular tissue. After imaging diagnostics, discussion of a multidisciplinary diagnostic and therapeutic team, the patient was offered a surgical procedure - widening of the excision margins to obtain oncological completeness and axillary lymphadenectomy. After the surgery, due to the results of the histopathological examination, complementary systemic treatment (chemo- and hormone therapy) and radiotherapy were used. Doctors often do not consider the possibility of primary breast cancer occurring elsewhere than in the breast. Breast imaging does not always make it possible to diagnose the disease, and doctors performing and interpreting these tests often do not include primary armpit cancer in the differential diagnosis. This can cause a delay in diagnosis and worsen the prognosis.

Sarcopenia is common in metastatic colorectal cancer (mCRC), increases the risk of treatment-related toxicity and reduces survival. Trifluridine/tipiracil (TT) chemotherapy significantly improved survival in refractory mCRC patients, but the prognostic and predictive role of pretherapeutic sarcopenia and variation in the skeletal muscle index (SMI) during this treatment has not been investigated so far. In this retrospective, observational study, clinical data on mCRC patients treated with TT at six cancer centres in Poland were collected. Computed tomography (CT) scans acquired at the time of initiation of TT (CT1) and on the first restaging (CT2), were evaluated. SMI was assessed based on the skeletal muscle area (SMA) at the level of the third lumbar vertebra. Progression-free survival (PFS) and overall survival (OS) were calculated from the treatment start. Neither initial sarcopenia nor ≥5% skeletal mass loss (SML) between CT1 and CT2 had a significant effect on PFS in treated patients (p = 0.5526 and p = 0.1092, respectively). In the multivariate analysis, reduced OS was found in patients with ≥5% SML (HR: 2.03 (1.11–3.72), p = 0.0039). We describe the prognostic role of sarcopenia beyond second line treatment and analyze other factors, such as performance status, tumor histological differentiation or carcinoembryonic antigen level that could predict TT treatment response.

Gallbladder cancer (GBC) is a highly malignant tumor with poorly understood etiology. An insight into phenotypic features of this malignancy may add to the knowledge of its carcinogenesis and pave the way to new therapeutic approaches. We assessed the expression of female sex hormone receptors (ERα, ERβ, PR), connective tissue growth factor (CTGF) and HER2 in GBC, and adjacent normal tissue (NT), and determined their prognostic impact. Immunohistochemical (IHC) expression of all biomarkers was performed in formalin-fixed, paraffin-embedded specimens in 60 Caucasian GBC patients (51 women and 9 men). ERβ, cytoPR and CTGF expression were found in 89%, 27%, 91% of GBC, and in 63%, 87%, 100% of NT, respectively. No ERα expression was found in GBC and NT. Strong (3+) HER2 expression by IHC or HER2 amplification was seen in five GBC (10.4%). A positive correlation was found between HER2 and CTGF and ERβ expression in GBC and matched NT. In the multivariate analysis, patient age >70 years, tumor size and ERβ expression in GBC was highly predictive for OS (p = 0.003). The correlation between HER2, CTGF and ERβ expression in GBC and NT may indicate the interaction of these pathways in physiological processes and gallbladder pathology.

Breast cancer is the most common cancer among women in Poland and worldwide; after lung cancer it is the second highest cause of death among females with malignancies. HER2 positive breast cancer occurs in ca.15–20% of all cases. More often than other subtypes, it affects younger patients and more often spreads metastasises to internal organs. The new drugs against the HER2 receptor significantly improve patients’ prognoses, regardless of the initial stage. The authors of the study involved 1503 patients with HER2 positive breast cancer from all stages (I–IV); 482 patients received preoperative systemic therapy (chemotherapy or hormonal therapy), 385 trastuzumab. Among the 1219 females qualified to surgery, 734 (60%) underwent a mastectomy, 485 (40%) had breast conserving therapy with adjuvant radiotherapy, some of them had preoperative systemic treatment.

Introduction. Tissue microarray (TMA) technique has been widely used, especially in immunohistochemical assays of new prognostic and predictive markers. The main objections raised by its opponents are the small amount of sampled material and the associated risk of inadequate assessment of analysed expression, resulting from the potential heterogeneity of tumour tissue. Material and methods. This study evaluated the compatibility of biomarker expression in two independent tissue cores, 1.5 mm in diameter, obtained by TMA technique from patients with gallbladder cancer (ERb, cytoPgR, HER2, CTGF) and ovarian cancer (PTEN, BCL2, PIK3CA, IGF1R). Comparison of the expression of individual biomarkers between cores was performed using the intraclass correlation coefficient (ICC), assuming a kappa < 0.4 as a weak, ≥ 0.4 as sufficient, ≥ 0.6 as good, and ≥ 0.75 as optimal correlation, and Kendall’s tau test — ICC package. Results. Evaluation of biomarker expression in the primary tumour was performed in 60 patients with gallbladder cancer and in 64 patients with high-grade serous ovarian cancer. Additionally, in patients with follicular cancer, the expression of the tested markers was assessed in the epithelium free from neoplastic malignancy. In both tumours, a good or sufficient level of homogeneity was observed in the expression of the analysed biomarkers between tissue cores. The correlation coefficient for the expression of individual markers in gallbladder cancer and adhering healthy tissue was: 0.68 (95% CI: 0.53–0.79)/0.62 (95% CI: 0.39–0.78) for ERb, 0.44 (95% CI: 0.23–0.61)/0.77 (95% CI: 0.61–0.87) for cytoPgR, 0.77 (95% CI: 0.65–0.85)/0.66 (95% CI: 0.44–0.80) for HER2, and 0.68 (95% CI: 0.53–0.79)/0.62 (95% CI: 0.39–0.78) for CTGF. In patients with ovarian cancer, the correlation coefficient within the primary tumour was 0.82 (95% CI: 0.71–0.89) for PTEN, 0.84 (95% CI: 0.75–0.90) for BCL2, 0.71 (95% CI: 0.56–0.81) for PIK3CA, and 0.77 (95% CI: 0.65–0.85) for IGF1R. Conclusions. Tissue microarray technique allows reliable assessment of the expression of tissue biomarkers within the primary tumour of gallbladder cancer and ovarian cancer

Background Oxaliplatin-based therapy with FOLFOX-4 or CAPOX administered over 6 months remains the standard adjuvant treatment for stage III colon cancer (CC) patients. However, many patients experience dose reduction or early termination of chemotherapy due to oxaliplatin toxicity, which may increase the risk of early recurrence. The objective of this study was to analyze the relationship between the relative dose intensity of oxaliplatin (RDI-O) and early recurrence among stage III CC patients. Methods The study included 365 patients treated at five oncology centers in Poland between 2000 and 2014. Survival analysis was performed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazard model; multivariate analysis was performed with the stepwise forward approach. For all analyses the α level of 0.05 was employed. Results The median follow-up was 51.8 months (range 8.2–115.1). Early recurrence p = 0.010), especially in low-risk group (HR = 1.56 (95%CI: 0.96–2.53), p = 0.07). In the multivariate analysis early recurrence was correlated with grade (OR = 2.47; 95% CI: 1.25–4.8; p = 0.008), pN (OR = 2.63; 95% CI: 1.55–4.54; p p = 0.013) and RDI-O (OR = 1.91; 95%CI: 1.06–3.39; p = 0.028). The early vs. late recurrence negatively correlated with OS regardless of the RDI-O (HR = 22.9 (95%CI: 13.9–37.6; p Conclusions RDI-O

Purpose The methods (IHC/FISH) typically used to assess ER, PR, HER2, and Ki67 in FFPE specimens from breast cancer patients are difficult to set up, perform, and standardize for use in low and middle-income countries. Use of an automated diagnostic platform (GeneXpert®) and assay (Xpert® Breast Cancer STRAT4) that employs RT-qPCR to quantitate ESR1, PGR, ERBB2, and MKi67 mRNAs from formalin-fixed, paraffin-embedded (FFPE) tissues facilitates analyses in less than 3 h. This study compares breast cancer biomarker analyses using an RT-qPCR-based platform with analyses using standard IHC and FISH for assessment of the same biomarkers. Methods FFPE tissue sections from 523 patients were sent to a College of American Pathologists-certified central reference laboratory to evaluate concordance between IHC/FISH and STRAT4 using the laboratory’s standard of care methods. A subset of 155 FFPE specimens was tested for concordance with STRAT4 using different IHC antibodies and scoring methods. Results Concordance between STRAT4 and IHC was 97.8% for ESR1, 90.4% for PGR, 93.3% for ERBB2 (IHC/FISH for HER2), and 78.6% for MKi67. Receiver operating characteristic curve (ROC) area under the curve (AUC) values of 0.99, 0.95, 0.99, and 0.85 were generated for ESR1, PGR, ERBB2, and MKi67, respectively. Minor variabilities were observed depending on the IHC antibody comparator used. Conclusion Evaluation of breast cancer biomarker status by STRAT4 was highly concordant with central IHC/FISH in this blinded, retrospectively analyzed collection of samples. STRAT4 may provide a means to cost-effectively generate standardized diagnostic results for breast cancer patients in low- and middle-income countries. Electronic supplementary material The online version of this article (10.1007/s10549-018-4889-5) contains supplementary material, which is available to authorized users.

BACKGROUNDPertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer.METHODSWe randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo.RESULTSIn the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P = 0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P = 0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P = 0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%).CONCLUSIONSPertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. (Funded by F. Hoffmann-La Roche/Genentech; APHINITY ClinicalTrials.gov number, NCT01358877.)

With increasing cancer rates, a steady rise is also observed in the numbers of such patients being followed-up after their treatment. This aspect of healthcare embraces cancer patients recovering from radical treatment, post-palliative treatment and frequently those patients who have exhausted the possibilities of specialist treatment. Controversies are ever ongoing about who should be responsible for monitoring post-treatment follow-up. Bearing in mind the limited numbers of specialists in clinical oncology, radiotherapy and cancer surgery, relative to GP specialists, the roles of GPs should be more boldly and clearly defined regarding the delivery of healthcare to cancer patients. Developing proficient ‘healthcare models’ based on collaboration between oncologists and GPs is thereby required. This article presents the arguments for justifying such a solution.

Overexpression of the receptor for human epidermal growth factor type 2 (HER2), or gene amplification for this receptor is observed in approx. 20–25% of breast cancer patients and is associated with a more aggressive course, a higher risk of recurrence and shorter survival. Trastuzumab, a monoclonal antibody, directed to the extracellular domain of the HER2 receptor, was introduced for the treatment of HER2-positive breast cancer in 1998, and its use has caused equal opportunities for patients with HER2-positive breast cancer and those with HER2-negative. In adjuvant treatment of early breast cancer the risk of recurrence is decreased and overall survival is prolonged. The results of international randomised studies, published more than 10 years ago, despite some controversies concerning optimal regimen and duration of treatment, almost immediately became the basis for a change in the standard of care. Currently we know that the optimal administration of trastuzumab is concurrent with taxane-based chemotherapy, but it should not be added to anthracyclines. Long-term observation of the patient population treated in these trials has shown that the introduction of trastuzumab to clinical practice has changed the natural history of HER2-positive early breast cancer. The benefit from this treatment lasts for many years.

Background: Clinical correlates of lapatinib resistance have not been well defined. Previous studies implicated genes regulated by the estrogen receptor (ER) and activation or mutation of proteins downstream from HER family receptors. In the current study, HER2 and HER3 expression levels were quantitatively measured using a VeraTag® fluorescence-based assay, in addition to seven downstream signaling proteins determined by IHC. All biomarkers were correlated with overall survival (OS) in patients treated with lapatinib. Methods: Formalin-fixed, paraffin-embedded samples were obtained from the primary tumor of 191 patients treated with lapatinib plus capecitabine following progression on trastuzumab. The HERmark® Breast Cancer Assay (Monogram Biosciences, South San Francisco) was used to quantify HER2 protein expression levels. HER3 protein expression was quantified using the VeraTag® technology (Monogram Biosciences). Expression of ER, PTEN, Cyclin E, HIF-2alpha, p-p70S6K, p-AMPK and p-MAPK were determined by IHC (Duchnowska et al., Oncotarget 2016; 7:550). OS analyses of HER2 and HER3 were stratified by key clinical variables, including stage and presence of a brain metastasis prior to lapatinib-based therapy. Results: Among the downstream signaling molecules, HIF-2alpha (r = -0.23; p = 0.047) and ER (r = -0.27; p = 0.005) were negatively correlated with HER2 expression after adjustment for multiple testing. PTEN appeared to correlate with HER3, but was not significant after adjustment for multiple testing. OS was significantly shorter for both those below the cut-off level of positivity by the HERmark assay (HR = 1.8; p = 0.029), and those with above median HER2 levels (HR = 1.7; p = 0.009), as compared to cases with in between levels. The relationship between HER2 and OS is also captured by a U-shaped, parabolic function in HER2 (p = 0.005). Elevated HER3 showed a trend toward a correlation with longer OS (HR = 0.66/log; p = 0.16), somewhat stronger in the ER-negative subset (HR = 0.55/log; p = 0.085) and in the subset with above-median HER2 (0.48/log; p = 0.10), where inhibiting HER2 activation of HER3 may be more important. In multivariate Cox models, HER2 (parabola, intermediate HER2 best, p = 0.001), presence of brain metastases (HR = 2; p < 0.001), ER (HR = 0.60; p = 0.009) and either p-p70S6K (HR = 0.66; p = 0.018) or p-AMPK (HR = 0.67; p = 0.022) were significantly associated with OS (p-p70S6K and p-AMPK were mutually correlated). Conclusions: Patients with moderately increased HER2 levels may have best outcomes while receiving lapatinib following progression on trastuzumab. This supports recent findings of a less benefit from lapatinib in patients with high HER2 expression (Nunciforo et al., SABCS 2015, P3-07-08). HER3 levels do not seem to substantially impact the prognosis. Further studies are warranted to explore the predictive utility of quantitative HER2 and HER3 in guiding HER2-directed therapies. Citation Format: Duchnowska R, Sperinde J, Czartoryska-Arlukowicz B, Mysliwiec P, Winslow J, Radecka B, Petropoulos C, Demlova R, Orlikowska M, Kowalczyk A, Lang I, Ziólkowska B, Debska-Szmich S, Merdalska M, Grela-Wojewoda A, Zawrocki A, Biernat W, Huang W, Jassem J. Predictive value of quantitative HER2 and HER3 levels combined with downstream signaling markers in HER2-positive advanced breast cancer patients treated with lapatinib [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-21.

Breast cancer (BC) in young women is rare, affecting only 4-6% of women under the age of 40. Regardless, BC remains the most common malignancy among younger patients. Recently, a significant increase in BC rates has been observed among pre-menopausal subjects. Breast cancer in young women requires special attention due to its specific morphologic and prognostic characteristics and unique aspects, including fertility preservation and psychosocial issues (e.g. its impact on family life and career). Young women are more likely to have tumors with higher incidence of negative clinicopathologic features (higher histological grade, more lymph node positivity, lower estrogen receptor (ER) positivity, higher rates of Her2/neu overexpression). Also, they tend to be diagnosed at more advanced stages of the disease. That, in turn, contributes to less favorable prognosis as compared to older women. Young women are generally treated similarly to older patients. Surgical management includes mastectomy or breast-conserving surgery, followed by radiation therapy (younger women have higher local recurrence rates than older women, especially after breast-conserving therapy). Although the basics of chemotherapy are the same for patients of all ages, younger women have some special considerations. It is important to consider options for fertility preservation before starting systemic treatment. Patients should have access to genetic testing as their results may affect the choice of therapy. Younger women and their families should receive adequate psychological support and counselling.

e12554 Background: ER negative (-)/PgR positive (+) breast cancer (BC) is very uncommon and questioned by many experts. We comprehensively reevaluated ER-/PgR+ BCs in the large cohort from Polish and Hungarian centers. Methods: FFPE blocks from 105 ER-/PgR+ tumors (45 breast biopsies and 64 post-operative samples from tumors not exposed to systemic therapy) were collected from 10 Polish and 3 Hungarian centers. In 60 cases available original slides with ER/PgR staining underwent reevaluation by 3 pathologists (MK, RP, WB) for ER and PgR expression by ASCO/CAP criteria. Subsequently, all samples were stained with 3 antibodies against ER (Dako monoclonal (MC) mouse anti-ERα, clone 1D5; Dako MC rabbit anti-ERα, clone EP1; VENTANA Roche MC rabbit anti-ERα, clone SP1), and PgR (Dako MC mouse anti-PgR, clone 636). If available, > 1 tissue block was used (av. 2.04 blocks/case, range 1-6). In 5 cases ESR1/PGR/ERBB2/MKi67 mRNA was measured by the Xpert® Breast Cancer STRAT4 (Cepheid, Sunnyvale, CA, USA). Results: 13 cases were excluded from immunohistochemical steps of the study due to insufficient amount of tissue and 8 - due to misdiagnosis after ER/PgR reevaluation of original slides. After re-staining, 42 cases (41.5%) retained the original phenotype, in 34 (33.67%) the ER status was corrected to ER+, and 16 (15.84%) tumors were ER/PgR-double-negative. The general agreement between anti-ER clones was moderate (Fleiss’ κ = 0.54). There were 56 ER- and 16 ER+ cases across all three assays. Five cases showed ER positivity with 2 antibodies (either SP1/EP1 or SP1/1D5), 5 tumors reacted exclusively with SP1 clone, and 2 - with 1D5 clone. Xpert Breast Cancer STRAT4 confirmed the ER-/PgR+ phenotype in 4 of 5 analyzed cases. The confirmed ER-/PgR+ BCs were characterized by lower percentage of PgR+ cells (median 5%) than BCs reclassified to ER+ (median 70%) (p = 0.022) and higher Ki67 expression than ER+ cases (median 54.5% vs 25%, respectively; p = 0.003). 39 (92.85%) ER-/PgR+ BCs presented with grade 3. Besides “conventional” high-grade cancers, we identified two distinct morphologies of ER-/PgR+ BC: resembling apocrine carcinoma (n = 5, 11.9%) and carcinoma with central acellular zone (n = 4, 9.5%). Conclusions: ER-/PgR+ BCs confirmed in the current study were defined by high-grade histology, high proliferation index and low percentage of PgR+ cells. We postulate ER-/PgR+ BC is a real albeit rare entity, and its diagnosis should be made cautiously, utilizing retesting with an alternative tissue block and anti-ER antibody.

// Renata Duchnowska 1 , Piotr J. Wysocki 2 , Konstanty Korski 3 , Bogumila Czartoryska-Arlukowicz 4 , Anna Niwinska 5 , Marlena Orlikowska 6 , Barbara Radecka 7 , Maciej Studzinski 8 , Regina Demlova 9 , Barbara Ziolkowska 10 , Monika Merdalska 11 , Łukasz Hajac 12 , Paulina Myśliwiec 13 , Dorota Zuziak 14 , Sylwia Debska-Szmich 15 , Istvan Lang 16 , Malgorzata Foszczynska-Kloda 2 , Bozenna Karczmarek-Borowska 17 , Anton Żawrocki 18 , Anna Kowalczyk 18 , Wojciech Biernat 18 , Jacek Jassem 18 , for the Central and East European Oncology Group (CEEOG) 1 Military Institute of Medicine, Oncology Department, Warsaw, Poland 2 West Pomeranian Cancer Center, Szczecin, Poland 3 Greater Poland Cancer Center, Poznan, Poland 4 Bialystok Oncology Center, Bialystok, Poland 5 The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 6 Warmia and Masuria Oncology Center, Olsztyn, Poland 7 Opole Oncology Center, Poland 8 Oncology Center, Bydgoszcz, Poland 9 Masaryk Memorial Cancer Institute, Brno, Czech Republic 10 Chemotherapy Department, Regional Hospital, Wroclaw, Poland 11 Oncology Center, Kielce, Poland 12 Oncology Center, Wroclaw, Poland 13 Oncology Center, Zielona Gora, Poland 14 Oncology Center, Bielsko-Biala, Poland 15 Medical University of Łodź, Łodź, Poland 16 Department of Medical Oncology, National Institute of Oncology, Budapest, Hungary 17 Department of Chemotherapy, Subcarpathian Oncology Center, Rzeszow, Poland 18 Medical University of Gdansk, Gdansk, Poland Correspondence to: Renata Duchnowska, e-mail: rdtt@wp.pl Keywords: breast cancer, epidermal growth factor receptor type 2, lapatinib, mTOR, p-MAPK Received: May 19, 2015 Accepted: November 13, 2015 Published: November 24, 2015 ABSTRACT Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25–0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06–3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13–2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29–6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43–0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48–7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25–7.58; p = 0.015). In conclusion: the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways – AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors.

Bones are the most common metastatic site of relapse in breast cancer patients and the prediction of bone metastases (BM) risk might prompt developing preventive and therapeutic strategies. The aim of the study was to correlate imumohistochemical (IHC) expression of selected proteins in primary breast cancer with the occurrence of BM. We analyzed expression of proteins potentially associated with BM in primary tumors of 184 patients with metastatic breast cancer (113 with- and 71 without BM). Expression of estrogen receptor (ER) in primary tumor was more common in patients with- compared to those without BM (74 vs. 45 % respectively, p = 0.0001), whereas in this subset less common was expression of parathyroid hormone related protein receptor type 1 (16 vs. 34 %, respectively, p = 0.007) and cytoplasmic expression of osteopontin (OPNcyt; 1.9 vs. 14 %, respectively, p = 0.002). The relationship between expression of ER and OPNcyt and the occurrence of BM was confirmed in the multivariate analysis. The ER-positive/OPNcyt negative phenotype was significantly more common in patients with- compared to those without BM (75 and 25 %, p