Biomarkers in breast cancer 2024: an updated consensus statement by the Spanish Society of Medical Oncology and the Spanish Society of Pathology.

This revised consensus statement of the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathological Anatomy (SEAP) updates the recommendations for biomarkers use in the diagnosis and treatment of breast cancer that we first published in 2018. The expert group recommends determining in early breast cancer the estrogen receptor (ER), progesterone receptor (PR), Ki-67, and Human Epidermal growth factor Receptor 2 (HER2), as well as BReast CAncer (BRCA) genes in high-risk HER2-negative breast cancer, to assist prognosis and help in indicating the therapeutic options, including hormone therapy, chemotherapy, anti-HER2 therapy, and other targeted therapies. One of the four available genetic prognostic platforms (Oncotype DX®, MammaPrint®, Prosigna®, or EndoPredict®) may be used in ER-positive patients with early breast cancer to establish a prognostic category and help decide with the patient whether adjuvant treatment may be limited to hormonal therapy. In second-line advanced breast cancer, in addition, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and estrogen receptor 1 (ESR1) should be tested in hormone-sensitive cases, BRCA gene mutations in HER2-negative cancers, and in triple-negative breast cancer (TNBC), programmed cell death-1 ligand (PD-L1). Newer biomarkers and technologies, including tumor-infiltrating lymphocytes (TILs), homologous recombination deficiency (HRD) testing, serine/threonine kinase (AKT) pathway activation, and next-generation sequencing (NGS), are at this point investigational.

Distribution of PD-L1, TROP2 and HER2- "lowness" in early triple-negative breast cancer: an opportunity for treatment de-escalation.

BACKGROUND: HER2, TROP2 and PD-L1 are novel targets in triple-negative breast cancer (TNBC). The combined expression status of these targets, and whether they can define prognostic subgroups, is currently undefined. METHODS: Immunohistochemistry was used to determine HER2, TROP2 and PD-L1 levels in 459 TNBC cases, that received in the adjuvant/neoadjuvant setting active surveillance, CMF, anthracycline-, anthracycline plus taxane-, or carboplatin-containing regimes. RESULTS: HER2-low patients with PD-L1 > 1 CPS (double-positive, herein "DP") had a mean PFS of 4768 days (95% CI: 4267-5268) versus 3522 days (95% CI: 3184-3861) for non-DP patients (P = 0.002). Regarding the received adjuvant treatment, DP patients (versus non-DP) receiving anthracyclines plus taxanes exhibited a mean PFS time of 4726 (95% CI: 4022-5430) versus 3302 (95% CI: 2818-3785) days (P = 0.039). Finally, 100% of DP patients that received a carboplatin-based regimen were long-term disease-free. CONCLUSIONS: Early HER2-low, PD-L1-positive TNBC patients have a very good prognosis, particularly if treated with anthracycline/taxane- or carboplatin-containing regimes.

Tumor P70S6K hyperactivation is inversely associated with tumor-infiltrating lymphocytes in triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is characterized by large heterogeneity and relative lack of available targeted therapies. To find therapeutic strategies for distinct patients with TNBC, several approaches have been used for TNBC clustering, including recently immune and phosphoproteomic patterns. Based on 70-kDa ribosomal protein S6 kinase (P70S6K)-TNBC clustering, the current study explores the immune profiling in TNBC tumors. METHODS: Stromal tumor-infiltrating lymphocytes (sTILs) were evaluated in human TNBC tumor samples. Furthermore, immunohistochemistry staining for CD8, CD4, Foxp3, and CD20 was performed in tissue microarrays (TMA) sections. RESULTS: Histological analysis showed decreased sTILs, CD20+ cells, and CD8+/CD4+ ratio in high phosphorylated P70S6K (p-P70S6K) tumors. Moreover, p-P70S6K score was directly correlated with CD4+ and Foxp3+ T cells, while it was inversely correlated with CD8+/CD4+ and CD8+/Foxp3+ ratios. CONCLUSION: sTIL infiltration and lymphocyte profiling vary in the context of hyperactivation of P70S6K in TNBC tumors.

Excess weight and anti-PD-1 immune checkpoint inhibitor's outcomes in non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibitors are one of the most effective treatments available in advanced non-small cell lung cancer. However, at present, there are no clinical or analytical biomarkers that define which patients benefit with certainty from these treatments. In our study, we evaluated whether excess weight could be a good predictive biomarker of benefit from these drugs. METHODS: We studied a population of 79 patients, divided into a study group with 39 patients diagnosed with non-small cell lung cancer treated with immunotherapy and 40 patients in a control group, diagnosed with different advanced cancers, treated with non-immunotherapy treatment. We analyzed according to the presence of excess weight or not, the treatment's outcome in the study group and in the control group (objective response, and progression-free and overall survival). RESULTS: In our study, we detected a better response rate to immunotherapy in patients with excess weight (62.50 vs 26.08%, OR 4.72, p = 0.02), and a better median progression-free survival (14.19 vs 5.03 months, HR 0.50, p = 0.058) and median overall survival (33.84 months vs 20.76 months, HR 0.43, p = 0.01) in the study group. These findings were specific to the immunotherapy group since in the control group, with patients who did not receive immune checkpoint inhibitors, these findings were not found. CONCLUSION: Our study suggests that patients with excess weight who receive anti-PD-1 immune checkpoint inhibitors diagnosed with non-small cell lung cancer have a better outcome. This effect is specific to patients receiving immunotherapy.

Consensus of the Spanish Society of Medical Oncology (SEOM) and Spanish Society of Pathology (SEAP) for HER2 testing in gastric carcinoma.

The identification of HER2 alterations in advanced gastric carcinomas is of critical importance in daily clinical practice as such neoplasms require specific treatment with trastuzumab. For these reasons, pathologists and oncologists with expertise in gastric carcinomas and HER2 testing from both organisations (SEAP and SEOM) have endeavoured to discuss and agree on national guidelines for HER2 testing in gastric carcinomas. These guidelines are based on the experience of those who participated in the discussions and also on experience published internationally. These agreed guidelines give the minimum requirements that a pathological anatomy laboratory must fulfil in order to guarantee adequate HER2 testing in daily practice. Any laboratories which do not meet the minimum standards set out in the guidelines must make every effort to achieve compliance.

Phase II study of trastuzumab and cisplatin as first-line therapy in patients with HER2-positive advanced gastric or gastroesophageal junction cancer.

INTRODUCTION: HER2 over-expression and/or amplification are present in 9-38% of gastric or gastroesophageal junction (GEJ) cancers and are correlated to poor outcome. We conducted a multicentre phase II trial to evaluate trastuzumab in combination with cisplatin in patients with untreated HER2-positive advanced gastric or GEJ cancer. MATERIALS AND METHODS: Chemo-naïve patients with measurable, non-resectable, advanced or metastatic gastric or GEJ adenocarcinoma, with HER2 over-expression and/or amplification (IHC 3+, or IHC 2+ and FISH+), age ≥18 years, ECOG ≤2, left ventricle ejection fraction ≥50% and adequate organ function were eligible. Treatment consisted of trastuzumab (8 mg/kg on cycle 1 day 1 as loading; 6 mg/kg in subsequent cycles) and cisplatin (75 mg/m(2)), both intravenously on day 1, every 21 days. RESULTS: Twenty-two out of 228 patients (10%) were HER2- positive and were included in this phase II trial. The median age was 66 years and ECOG 0/1 was 41%/59%. The median number of cycles was 4 (range 1-41). The confirmed ORR was 32% and disease control was achieved in 64% of patients. Median time to progression was 5.1 months. Grade 3 adverse events included asthenia (27%), neutropenia (18%), anorexia (14%), diarrhoea (9%) and abdominal pain (9%). There were no grade 4 toxicities or treatment-related deaths. Higher baseline HER extracellular domain (ECD) levels were associated with better outcome in terms of response and survival. CONCLUSIONS: Trastuzumab in combination with cisplatin is an active regimen and has a favourable toxicity profile in advanced HER2-positive gastric or gastroesophageal cancers.

Targeting cytoskeleton reorganisation as antimetastatic treatment.

Metastatic relapse is responsible for 90% of cancer-related deaths. The process of distant spreading is a cascade of events that is regulated in a highly complex manner; one cellular phenomenon underlying all the events is cytoskeletal reorganisation. Despite the fact that the ability to leave the primary site and establish a viable mass in a distant site is a hallmark of cancer, targeting cytoskeletal reorganisation is an emerging field. In this review we describe the key signalling pathways controlling cytoskeletal reorganisation and the current targeted therapies against the "druggable" nodes. Finally, we discuss potential implications of trial design that can play a role in detecting the specific activity of this drug class.

Selection of extreme phenotypes: the role of clinical observation in translational research.

Systematic collection of phenotypes and their correlation with molecular data has been proposed as a useful method to advance in the study of disease. Although some databases for animal species are being developed, progress in humans is slow, probably due to the multifactorial origin of many human diseases and to the intricacy of accurately classifying phenotypes, among other factors. An alternative approach has been to identify and to study individuals or families with very characteristic, clinically relevant phenotypes. This strategy has shown increased efficiency to identify the molecular features underlying such phenotypes. While on most occasions the subjects selected for these studies presented harmful phenotypes, a few studies have been performed in individuals with very favourable phenotypes. The consistent results achieved suggest that it seems logical to further develop this strategy as a methodology to study human disease, including cancer. The identification and the study with high-throughput techniques of individuals showing a markedly decreased risk of developing cancer or of cancer patients presenting either an unusually favourable prognosis or striking responses following a specific treatment, might be promising ways to maximize the yield of this approach and to reveal the molecular causes that explain those phenotypes and thus highlight useful therapeutic targets. This manuscript reviews the current status of selection of extreme phenotypes in cancer research and provides directions for future development of this methodology.

Spanish Society of Medical Oncology consensus on the use of erythropoietic stimulating agents in anaemic cancer patients.

Treatment of anaemia is a very important aspect in the management of cancer patients. In order to carry out a consensus process about the use of erythropoietic stimulating agents (ESAs) in cancer patients, the Spanish Society of Medical Oncology (SEOM) elaborated a working group which coordinated a panel of medical oncology specialists. This working group has reviewed the main issues about the use of ESAs. In addition a consensus meeting was held in Madrid on 25 April 2007. The following conclusions were made: Since ESA treatment increases the haemoglobin (Hb) level and decreases the red blood cell (RBC) transfusion requirements, ESAs should be used within the approved indications in patients undergoing chemotherapy treatment, beginning at a Hb level below 11 g/dl and maintaining it around 12 g/dl, with iron supplements if necessary. Neither increasing the ESA dose in nonresponders nor the use of ESAs in the treatment of chronic cancer-related anaemia is recommended.

Guidelines for HER2 testing in breast cancer: a national consensus of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM).

Identifying breast cancers with HER2 overexpression or amplification is critical as these usually imply the use of HER2-targeted therapies. DNA (amplification) and protein (overexpression) HER2 abnormalities usually occur simultaneously and both in situ hybridisation and immunohistochemistry may be accurate methods for the evaluation of these abnormalities. However, recent studies, including those conducted by the Association for Quality Assurance of the Spanish Society of Pathology, as well as the experience of a number of HER2 testing National Reference Centres have suggested the existence of serious reproducibility issues with both techniques. To address this issue, a joint committee from the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) was established to review the HER2 testing guidelines. Consensus recommendations are based not only on the panellists' experience, but also on previous consensus guidelines from several countries, including the USA, the UK and Canada. These guidelines include the minimal requirements that pathology departments should fulfil in order to guarantee proper HER2 testing in breast cancer. Pathology laboratories not fulfilling these standards should make an effort to meet them and, until then, are highly encouraged to submit to reference laboratories breast cancer samples for which HER2 determination has clinical implications for the patients.

An easy, rapid and objective mathematical method to identify fatty acid synthase (oncogenic antigen-519) modulators with potential anticancer value.

Fatty acid synthase (FASN) is a novel druggable target for metabolically treating and preventing human malignancies. We envisioned that if loss of sensitivity to C75 (a slow-binding FASN inhibitor) occurs in parallel with loss of FASN expression and/or activity, a mathematical assessment of the nature of the interaction between investigational FASN modulators and C75 may predict the ability of experimental compounds to regulate FASN. We statistically compared the arithmetical sums of the anti-proliferative effects obtained when FASN modulators and C75 were used as single agents to those observed experimentally when agents were actually combined in a sequential schedule (i.e., FASN modulator-->C75). A reduced sensitivity to C75 (antagonism) occurred when compounds down-regulated FASN activity/expression, while an enhanced C75 efficacy (synergism) was found following exposure to FASN up-regulators. This "C75-sensitivity test" might offer an easy, rapid and objective method to identify FASN inhibitors with potential anticancer value in human cancer.

HER2 (erbB-2)-targeted effects of the omega-3 polyunsaturated fatty acid, alpha-linolenic acid (ALA; 18:3n-3), in breast cancer cells: the "fat features" of the "Mediterranean diet" as an "anti-HER2 cocktail".

BACKGROUND: Data derived from epidemiological and experimental studies suggest that alphalinolenic acid (ALA; 18:3n-3), the main omega-3 polyunsaturated fatty acid (PUFA) present in the Western diet, may have protective effects in breast cancer risk and metastatic progression. A recent pilot clinical trial assessing the effects of ALA-rich dietary flaxseed on tumor biological markers in postmenopausal patients with primary breast cancer demonstrated significant reductions in tumor growth and in HER2 (erbB-2) oncogene expression. HYPOTHESIS: The molecular mechanism by which ALA inhibits breast cancer cell growth and metastasis formation may involve a direct regulation of HER2, a well-characterized oncogene playing a key role in the etiology, progression and response to some chemo- and endocrine therapies in approximately 20% of breast carcinomas. METHODS: Using HER2-specific ELISA, flow cytometry, immunofluorescence microscopy, Western blotting, RT-PCR and HER2 promoter-reporter analyses, we characterized the effects of exogenous supplementation with ALA on the expression of HER2 oncogene, a master key player in the onset and metastasis formation of breast cancer disease. Metabolic status (MTT) assays were performed to evaluate the nature of the cytotoxic interaction between ALA and the humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin). To study these issues we used BT-474 and SKBr-3 breast cancer cells, which naturally exhibit amplification of the HER2 oncogene. RESULTS: ALA treatment dramatically suppressed the expression of HER2-coded p185Her-2/neu oncoprotein as determined by ELISA, flow cytometry, immunofluorescence microscopy and immunoblotting techniques. Interestingly, ALA-induced down-regulation of p185Her-2/neu correlated with a transcriptional response as no HER2 mRNA signal could be detected by RT-PCR upon treatment with optimal concentrations of ALA (up to 20 microM). Consistent with these findings, ALA exposure was found to dramatically repress the activity of a Luciferase reporter gene driven by the HER2 promoter. Moreover, the nature of the cytotoxic interaction between ALA and trastuzumab (Herceptin) revealed a significant synergism as assessed by MTT-based cell viability assays. CONCLUSIONS: i) These findings reveal that the omega-3 PUFA ALA suppresses overexpression of HER2 oncogene at the transcriptional level, which, in turn, interacts synergistically with anti-HER2 trastuzumab- based immunotherapy. ii) Our results molecularly support a recent randomized double-blind placebo-controlled clinical trial suggesting that ALA may be a potential dietary alternative or adjunct to currently used drugs in the management of HER2-positive breast carcinomas. iii) Considering our previous findings demonstrating the <> of the omega-6 PUFA linolenic acid (LA; 18:2n-6) and the <> of the omega-3 PUFA docosahexaenoic acid (DHA; 22:6n-3) and of the omega-9 monounsaturated fatty acid oleic acid (OA; 18:1n-9), it is reasonable to suggest that a low omega-6/omega-3 PUFA ratio and elevated MUFA levels, the two prominent <> of the <>, should be extremely efficient at blocking HER2 expression in breast cancer cells.

Serum endostatin and bFGF as predictive factors in advanced breast cancer patients treated with letrozole.

INTRODUCTION: To investigate the value of baseline serum levels of VEGF, bFGF, endostatin and their ratio as predictive factors of response to endocrine therapy in patients with metastatic breast cancer (MBC) and positive ER treated with letrozole after tamoxifen failure. MATERIALS AND METHOD: The serum levels of endostatin, VEGF and bFGF were determined in postmenopausal patients with progressing MBC from serum samples obtained before initiation of letrozole. The relation between serum angiogenic factor levels and TTP was investigated. RESULTS: Seventy-six patients (45.2%) presented a high endostatin level (> 24.6 ng/ml), 40% low bFGF levels (0 pg/ml) and 50.4% low VEGF (=/< 187 ng/ml). With a median follow-up of 22 months, the median TTP was 12.3 months. Median TTP was worse in patients with high endostatin concentration as well as in the low bFGF group, but was not affected when VEGF was considered. When the two factors were combined, the median TTP of patients with endostatin > 24.6 ng/ml and bFGF equal 0 pg/ml was 9.5 months versus 19.5 months in patients with endostatin =/< 24.6 ng/ml and bFGF > 0 pg/ml. CONCLUSIONS: The baseline levels of bFGF and endostatin are predictive factors of efficacy in patients with MBC treated with letrozole and can select groups with different TTP.

Mediterranean diet, olive oil and cancer.

Olive oil is an integral ingredient of the "Mediterranean diet" and accumulating evidence suggests that it may have a potential role in lowering the risk of several types of cancers. The mechanisms by which the cancer-preventing effects of olive oil can be performed, however, are not known. We recently hypothesized that a novel molecular explanation concerning the anti-cancer actions of olive oil may relate to the ability of its monounsaturated fatty acid (MUFA) oleic acid (OA; 18:1n-9) to specifically regulate cancer-related oncogenes. Supporting our hypothesis, exogenous supplementation of cultured breast cancer cells with physiological concentrations of OA was found to suppress the overexpression of HER2 (Her-2/neu, erbB-2), a well-characterized oncogene playing a key role in the etiology, progression and response to chemotherapy and endocrine therapy in approximately 20% of breast carcinomas. OA treatment was also found to synergistically enhance the efficacy of trastuzumab, a humanized monoclonal antibody binding with high affinity to the ectodomain (ECD) of the Her2-coded p185(HER2) oncoprotein. Moreover, OA exposure significantly diminished the proteolytic cleavage of the ECD of HER2 and, consequently, its activation status, a crucial molecular event that determines both the aggressive behavior and the response to trastuzumab of Her2-overexpressing breast carcinomas. Our most recent findings further reveal that OA exposure may suppresses HER2 at the transcriptional level by up-regulating the expression of the Ets protein PEA3 -a DNA-binding protein that specifically blocks HER2 promoter activity- in breast, ovarian and stomach cancer cell lines. This anti-HER2 property of OA offers a previously unrecognized molecular mechanism by which olive oil may regulate the malignant behavior of cancer cells. From a clinical perspective, it could provide an effective means of influencing the outcome of Her-2/neu-overexpressing human carcinomas with poor prognosis. Indeed, OA-induced transcriptional repression of HER2 oncogene may represent a novel genomic explanation linking "Mediterranean diet", olive oil and cancer as it seems to equally operate in various types of Her-2/neu-related carcinomas.

Interstitial pneumonitis after oxaliplatin treatment in colorectal cancer.

Progressive respiratory failure developed in a 68 year-old female who was treated with single-agent oxaliplatin for colorectal cancer. Only one cycle of 5-fluorouracil had been previously administered. Computed tomography of the chest showed lesions that suggested pulmonary fibrosis. There was an unfavourable response to treatment with corticosteroids, antimicrobial and antifungical agents. Lung biopsy findings were compatible with interstitial pneumonitis. The patient died 20 days after admission due to irreversible respiratory failure. This is the first case reported in the literature of interstitial pneumonitis related to single-agent oxaliplatin administration.