3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial.

BACKGROUND: PHERGain was designed to assess the feasibility, safety, and efficacy of a chemotherapy-free treatment based on a dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer (EBC). It used an 18fluorine-fluorodeoxyglucose-PET-based, pathological complete response (pCR)-adapted strategy. METHODS: PHERGain was a randomised, open-label, phase 2 trial that took place in 45 hospitals in seven European countries. It randomly allocated patients in a 1:4 ratio with centrally confirmed, HER2-positive, stage I-IIIA invasive, operable breast cancer with at least one PET-evaluable lesion to either group A, where patients received docetaxel (75 mg/m2, intravenous), carboplatin (area under the curve 6 mg/mL per min, intravenous), trastuzumab (600 mg fixed dose, subcutaneous), and pertuzumab (840 mg loading dose followed by 420 mg maintenance doses, intravenous; TCHP), or group B, where patients received trastuzumab and pertuzumab with or without endocrine therapy, every 3 weeks. Random allocation was stratified by hormone receptor status. Centrally reviewed PET was conducted at baseline and after two treatment cycles. Patients in group B were treated according to on-treatment PET results. Patients in group B who were PET-responders continued with trastuzumab and pertuzumab with or without endocrine therapy for six cycles, while PET-non-responders were switched to receive six cycles of TCHP. After surgery, patients in group B who were PET-responders who did not achieve a pCR received six cycles of TCHP, and all patients completed up to 18 cycles of trastuzumab and pertuzumab. The primary endpoints were pCR in patients who were group B PET-responders after two treatment cycles (the results for which have been reported previously) and 3-year invasive disease-free survival (iDFS) in patients in group B. The study is registered with ClinicalTrials.gov (NCT03161353) and is ongoing. FINDINGS: Between June 26, 2017, and April 24, 2019, a total of 356 patients were randomly allocated (71 patients in group A and 285 patients in group B), and 63 (89%) and 267 (94%) patients proceeded to surgery in groups A and B, respectively. At this second analysis (data cutoff: Nov 4, 2022), the median duration of follow-up was 43·3 months (range 0·0-63·0). In group B, the 3-year iDFS rate was 94·8% (95% CI 91·4-97·1; p=0·001), meeting the primary endpoint. No new safety signals were identified. Treatment-related adverse events and serious adverse events (SAEs) were numerically higher in patients allocated to group A than to group B (grade ≥3 62% vs 33%; SAEs 28% vs 14%). Group B PET-responders with pCR presented the lowest incidence of treatment-related grade 3 or higher adverse events (1%) without any SAEs. INTERPRETATION: Among HER2-positive EBC patients, a PET-based, pCR-adapted strategy was associated with an excellent 3-year iDFS. This strategy identified about a third of patients who had HER2-positive EBC who could safely omit chemotherapy. FUNDING: F Hoffmann-La Roche.

Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase. METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety. RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group. CONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).

Adipocyte Microenvironment in Ovarian Cancer: A Critical Contributor?

Ovarian cancer is one of the most common gynecological malignancies and has low survival rates. One of the main determinants of this unfavorable prognosis is the high rate of peritoneal metastasis at diagnosis, closely related to its morbidity and mortality. The mechanism underlying peritoneal carcinomatosis is not clearly defined, but a clear preference for omental spread has been described. Growing evidence suggests that adipose tissue plays a role in promoting cancer onset and progression. Moreover, obesity can lead to changes in the original functions of adipocytes, resulting in metabolic and inflammatory changes in the adipose tissue microenvironment, potentially increasing the risk of tumor growth. However, the specific roles of adipocytes in ovarian cancer have not yet been fully elucidated. Due to the undeniable link between obesity and cancer, the adipose tissue microenvironment could also present a promising therapeutic target that warrants further research. This review discusses the complex relationship between ovarian cancer and the adipose tissue microenvironment.

Trastuzumab and pertuzumab without chemotherapy in early-stage HER2+ breast cancer: a plain language summary of the PHERGain study.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a publication about the PHERGain study, which was published in The Lancet Oncology in May 2021. The study includes 376 women with a type of breast cancer called HER2-positive breast cancer that can be removed by surgery. In the study, researchers wanted to learn if participants could be treated with two medicines called trastuzumab and pertuzumab without the need for chemotherapy. To identify HER2-positive tumors with more sensitivity to anti-HER2 therapies, the researchers used a type of imaging called a FDG-PET scan to check how well the treatments were working. WHAT HAPPENED IN THE PHERGAIN STUDY?: Participants took a treatment before surgery, consisting of either chemotherapy (docetaxel and carboplatin) plus trastuzumab and pertuzumab (group A) or trastuzumab and pertuzumab alone (plus hormone therapy if the tumor was hormone receptor-positive; group B). After two cycles of treatment, participants underwent a FDG-PET scan. Participants assigned to group A completed 6 cycles of treatment regardless of 18F-FDG-PET results. Participants in group B continued the same treatment until surgery if their FDG-PET scan showed the treatment was working. While participants who did not show a response started treatment with chemotherapy in addition to trastuzumab and pertuzumab. All participants then had surgery. WHAT WERE THE RESULTS?: The results revealed that, of the participants in group B who showed a response using FDG-PET scan, 37.9% achieved a disappearance of all invasive cancer in the breast and axillary lymph nodes. This rate appears to be higher than those reported in previous studies evaluating the same treatment. These participants also had less side effects and improved overall quality of life compared with participants taking chemotherapy plus trastuzumab and pertuzumab. WHAT DO THE RESULTS OF THE STUDY MEAN?: Early monitoring of how well participants respond to treatment by FDG-PET scan seems to identify participants with operable HER2-positive breast cancer who were more likely to benefit from trastuzumab and pertuzumab without the need to have chemotherapy. The PHERGain study is still ongoing and results on long-term survival are expected to be released in 2023. Clinical Trial Registration: NCT03161353 (ClinicalTrials.gov).

Staining of E-selectin ligands on paraffin-embedded sections of tumor tissue.

BACKGROUND: The E-selectin ligands expressed by cancer cells mediate adhesion of circulating cancer cells to endothelial cells, as well as within tissue microenvironments important for tumor progression and metastasis. The identification of E-selectin ligands within cancer tissue could yield new biomarkers for patient stratification and aid in identifying novel therapeutic targets. The determinants of selectin ligands consist of sialylated tetrasaccharides, the sialyl Lewis X and A (sLeX and sLeA), displayed on protein or lipid scaffolds. Standardized procedures for immunohistochemistry make use of the antibodies against sLeX and/or sLeA. However, antibody binding does not define E-selectin binding activity. METHODS: In this study, we developed an immunohistochemical staining technique, using E-selectin-human Ig Fc chimera (E-Ig) to characterize the expression and localization of E-selectin binding sites on paraffin-embedded sections of different cancer tissue. RESULTS: E-Ig successfully stained cancer cells with high specificity. The E-Ig staining show high reactivity scores in colon and lung adenocarcinoma and moderate reactivity in triple negative breast cancer. Compared with reactivity of antibody against sLeX/A, the E-Ig staining presented higher specificity to cancer tissue with better defined borders and less background. CONCLUSIONS: The E-Ig staining technique allows the qualitative and semi-quantitative analysis of E-selectin binding activity on cancer cells. The development of accurate techniques for detection of selectin ligands may contribute to better diagnostic and better understanding of the molecular basis of tumor progression and metastasis.

Beta-Adrenergic Blockade in Advanced Non-Small Cell Lung Cancer Patients Receiving Immunotherapy: A Multicentric Study.

Introduction The standard treatment of cancer has dramatically improved with immune checkpoint inhibitors (ICIs). Despite their proven advantage, many patients fail to exhibit a meaningful and lasting response. The beta-adrenergic signalling pathway may hold significant promise due to its role in promoting an immunosuppressive milieu within the tumour microenvironment. Inhibiting ß-adrenergic signalling could enhance ICI activity; however, blocking this pathway for this purpose has yielded conflicting results. The primary objective of this study was to evaluate the effect of beta-blocker use on overall survival and progression-free survival during ICI therapy. Methods A multicentric, retrospective, observational study was conducted in four Portuguese institutions. Patients with advanced non-small cell lung cancer treated with ICIs between January 2018 and December 2019 were included. Those using beta blockers for non-oncological reasons were compared with non-users. Results Among the 171 patients included, 36 concomitantly received beta blockers and ICIs. No significant increase was found in progression-free survival among patients who took ß-blockers (HR 0.74, 95% confidence interval (CI) 0.48-1.12, p = 0.151), and no statistically significant difference was found in overall survival. An apparent trend was observed towards better outcomes in the beta-blocker group, with a median overall survival of 9.93 months in the group not taking ß-blockers versus 14.90 months in the ß-blocker group (p = 0.291) and a median progression-free survival of 5.37 in the group not taking ß-blockers versus 10.87 months in the ß-blocker group (p = 0.151). Nine (25%) patients in the beta-blocker group and 16 (12%) in the non-beta-blocker group were progressive disease-free at the end of follow-up. This difference between the two groups is statistically significant (p = 0.047). Conclusion Our study found no statistically significant evidence that beta blockers enhance the effectiveness of immunotherapy. Using adrenergic blockade to modulate the immune system shows promise, warranting the need to develop prospective clinical studies.

Optimal [18F]FDG PET/CT Cutoff for Pathologic Complete Response in HER2-Positive Early Breast Cancer Patients Treated with Neoadjuvant Trastuzumab and Pertuzumab in the PHERGain Trial.

The PHERGain trial investigated the potential of metabolic imaging to identify candidates for chemotherapy deescalation in human epidermal growth factor receptor 2 (HER2)-positive, invasive, operable breast cancer with at least 1 breast lesion evaluable by [18F]FDG PET/CT. [18F]FDG PET/CT responders were defined as patients with an SUVmax reduction (ΔSUVmax) of at least 40% in all of their target lesions after 2 cycles of trastuzumab and pertuzumab (HP) (with or without endocrine therapy). In total, 227 of 285 patients (80%) included in the HP arm showed a predefined metabolic response and received a total of 8 cycles of HP (with or without endocrine therapy). Pathologic complete response (pCR), defined as ypT0/isN0, was achieved in 37.9% of the patients. Here, we describe the secondary preplanned analysis of the best cutoff of ΔSUVmax for pCR prediction. Methods: Receiver-operating-characteristic analysis was applied to look for the most appropriate ΔSUVmax cutoff in HER2-positive early breast cancer patients treated exclusively with neoadjuvant HP (with or without endocrine therapy). Results: The ΔSUVmax capability of predicting pCR in terms of the area under the receiver-operating-characteristic curve was 72.1% (95% CI, 65.1-79.2%). The optimal ΔSUVmax cutoff was found to be 77.0%, with a 51.2% sensitivity and a 78.7% specificity. With this cutoff, 74 of 285 patients (26%) would be classified as metabolic responders, increasing the pCR rate from 37.9% (cutoff ≥ 40%) to 59.5% (44/74 patients) (P < 0.01). With this optimized cutoff, 44 of 285 patients (15.4%) would avoid chemotherapy in either the neoadjuvant or the adjuvant setting compared with 86 of 285 patients (30.2%) using the original cutoff (P < 0.001). Conclusion: In the PHERGain trial, an increased SUVmax cutoff (≥77%) after 2 cycles of exclusive HP (with or without endocrine therapy) achieves a pCR in the range of the control arm with chemotherapy plus HP (59.5% vs. 57.7%, respectively), further identifying a subgroup of patients with HER2-addicted tumors. However, the original cutoff (≥40%) maximizes the number of patients who could avoid chemotherapy.

Sialyl LewisX/A and Cytokeratin Crosstalk in Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) encompasses multiple entities and is generally highly aggressive and metastatic. We aimed to determine the clinical and biological relevance of Sialyl-Lewis X and A (sLeX/A)-a fucosylated glycan involved in metastasis-in TNBC. Here, we studied tissues from 50 TNBC patients, transcripts from a TNBC dataset from The Cancer Genome Atlas (TCGA) database, and a primary breast cancer cell line. All 50 TNBC tissue samples analysed expressed sLeX/A. Patients with high expression of sLeX/A had 3 years less disease-free survival than patients with lower expression. In tissue, sLeX/A negatively correlated with cytokeratins 5/6 (CK5/6, which was corroborated by the inverse correlation between fucosyltransferases and CK5/6 genes. Our observations were confirmed in vitro when inhibition of sLeX/A remarkably increased expression of CK5/6, followed by a decreased proliferation and invasion capacity. Among the reported glycoproteins bearing sLeX/A and based on the STRING tool, α6 integrin showed the highest interaction score with CK5/6. This is the first report on the sLeX/A expression in TNBC, highlighting its association with lower disease-free survival and its inverse crosstalk with CK5/6 with α6 integrin as a mediator. All in all, sLeX/A is critical for TNBC malignancy and a potential prognosis biomarker and therapeutic target.

Correction: Association of Tumor-Infiltrating Lymphocytes With Survival in Stages II and III Colorectal Cancer.

[This corrects the article DOI: 10.7759/cureus.31144.].

Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement. METHODS: This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs, and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n = 8; cohort 1), asymptomatic untreated BMs (n = 4; cohort 2), or progressing BMs after local therapy (n = 9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial objective response rate (ORR-IC) for cohorts 2 and 3. RESULTS: As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P < .001). ORR-IC was 50.0% (95%CI, 6.7-93.2) in cohort 2 and 44.4% (95%CI, 13.7-78.8; P < .001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2-74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0-86.7), 80.0% (95%CI, 28.4-99.5) in cohort 1, 50.0% (95%CI, 6.7-93.2) in cohort 2, and 66.7% (95%CI, 29.9-92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade ≥3), nausea (42.9%; 0% grade ≥3), neutropenia (28.6%; 19% grade ≥3), and constipation (28.6%; 0% grade ≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis. CONCLUSIONS: T-DXd showed intracranial activity with manageable toxicity and maintained the quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.

Non-endometrioid endometrial cancer: Analysis of different adjuvant treatment modalities.

BACKGROUND: Adjuvant treatment for endometrial carcinoma (EC) is decided based on risk assessment. Tumors of non-endometrioid (NE) histology are classified as high-risk and adjuvant treatment is recommended. MATERIALS AND METHODS: We analyzed retrospectively all NEEC patients treated in two Portuguese oncology centers, between 2009 and 2018. Comparison of adjuvant modalities were performed by overall survival (OS) and disease-free survival (DFS) analysis. RESULTS: A total of 66 patients were included, with mean age 69 years. Serous histology was found in 34 patients (51.5%), clear-cell in 13 (19.7%) and carcinosarcoma in 18 (27.3%). Based on FIGO staging-system, 34 (51.5%) patients were diagnosed at stages III-IV. Following surgery, no further treatment was performed in 16 patients (24.4%), 11 (16.7%) received isolated chemotherapy (CT), 11 (16.7%) isolated radiotherapy (RT) and 28 (42.4%) combination therapy (CT+RT). Kaplan-Meier analysis showed higher median (m)DFS in the CT+RT group: 30.7 months (m) compared to RT alone: 14.1 m. The mDFS of the isolated CT group was 10.8 m and for patients with no further treatment it was 5.7 m, p = 0.03. Median OS was also increased in the combination group CT+RT (78.3 m) compared to isolated RT (64.3 m), isolated CT (37.3 m) and no further treatment (46.7 m), p=0.005. Multivariate Cox-regression using CT+RT as reference, showed hazard-ratio of 3.5 (p = 0.05) and 4.5 (p = 0.01) for the CT and for no-treatment group respectively. CONCLUSIONS: In NEEC patients, DFS and OS analysis showed better prognosis in combination of CT+RT. Patients that underwent only RT had better survival outcomes when compared to those treated with CT only.

Refining Therapy in Patients with HER2-Positive Breast Cancer with Central Nervous System Metastasis.

Background: Brain metastasis (BM) is a major clinical problem in metastatic breast cancer (MBC), occurring in 50% of patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Historically omitted from clinical trials, recent studies of novel HER2-targeted agents have focused on HER2+ BM patients, addressing stable but also progressing BM and leptomeningeal carcinomatosis (LMC). Summary: This review aimed to summarize the most relevant data on treating patients with HER2+ BM and LMC. Key Messages: The treatment paradigm for patients with HER2+ MBC has changed. Local therapies play an important role, but accumulating evidence on the intracranial activity and clinical benefit of anti-HER2 targeting therapies might lead to a shift in the paradigm on treating BM in the next few years towards more widespread use of systemic therapy.

Association of Tumor-Infiltrating Lymphocytes With Survival in Stages II and III Colorectal Cancer.

The tumor microenvironment is crucial in tumourigenesis, response to therapy, and elimination of tumor cells. Tumor-infiltrating lymphocytes (TILs) promote the host immune response and are associated with a better prognosis in colorectal cancer (CRC). This multicentric retrospective study evaluated the relationship between the presence and intensity of TILs and survival outcomes. A total of 651 patients from four Portuguese oncological centers who underwent surgical resection for stages II or III colorectal adenocarcinoma between 2016 and 2019 were included in this study. The mean age of the study population was 70 years; 58.2% were males. The median overall survival was 58.03 ± 1.29 months (95% confidence interval (CI) 55.50 - 60.56), and the median disease-free survival (DFS) was 53.02 ± 1.39 months (95% CI 50.29 - 55.74). Patients with high infiltrate (including those with moderate, abundant, or Crohn-like infiltrate) had significantly longer DFS i.e., 58.48 ± 1.84 months (95% CI 54.87 - 62.09 months) vs 49.22 ± 1.75 months (95% CI 45.79 - 52.64 months) in the group with absent or minimal infiltrate; p = 0.003. Assessing the side of the tumor, high infiltrate was associated with higher DFS (59.86 ± 2.36 months (95% CI 55.23 - 64.50 months) vs 49.60 ± 2.40 months (95% CI 44.90 - 54.29 months), p = 0.011). This work reinforces the importance of research into possible prognostic and predictive factors in patients with CRC.

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab.

Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood-brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis (LC) and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25 mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung, and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab, and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after LC diagnosis. A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule, and duration of treatment.

Uterine Sarcomas: A Retrospective Analysis of a Cohort of 62 Patients.

Background and objective Uterine sarcomas are rare tumors, and they account for 4% of all uterine malignancies. These tumors are characterized by a great diversity of histological types, and current knowledge regarding their treatment is limited. The aim of our study was to analyze a cohort of patients with uterine sarcomas with respect to the histological types of their tumors, as well as their prognosis and treatment. Materials and methods This was a retrospective analysis involving patients diagnosed at a single center with uterine sarcoma between 2003 and 2017.  Results The study included 62 patients; the mean age of the patients was 62 ±13 years. Carcinosarcoma was identified in 44% of cases, leiomyosarcoma in 40%, and endometrial stromal sarcoma in 13%. Endometrial stromal sarcoma was found to occur in younger women compared to carcinosarcoma (52 ±13 vs. 66 ±12 years, p=0.016); 90% of patients underwent surgery, and medical treatment was implemented in 42%. The mean overall survival (OS) was 93 ±10.65 months, and the median progression-free survival (PFS) was 12 months. There was a significant association between the stage of the disease at diagnosis and the probability of survival: mean OS was 118 months for locoregional disease vs. 44 months for metastatic disease (p<0.001). The overall five-year survival rate was 39%. Discussion and conclusions Uterine sarcomas are rare cancers, and they are very heterogeneous. They are also associated with a high mortality rate. Further investigational studies are required so that a more effective treatment method and individualized treatment plans can be implemented for patients with uterine sarcoma.

Next-Generation Sequencing in Breast Cancer Management: A Case Report of Genomic Tumour Evolution over Time.

The clinicopathological breast cancer subtypes are used in clinical practice to better anticipate biological behaviour and guide systemic treatment strategy. In the adjuvant setting, genomic assay recurrence scores became widely available for luminal-like disease. Recently, next-generation sequencing (NGS) platforms have been used, essentially, in more advanced disease setting, in situations refractory to conventional treatment, or even in rare cancers for which there are no established treatment guidelines. Moreover, subpopulations of cancer cells with unique genomes within the same patient may exist across different regions of a tumour or evolve over time, which is called intratumoural heterogeneity. We herein report a case of a 38-year-old woman with breast cancer whose primary and metastatic disease exhibited discordant expression of hormone receptors, with the former being positive and the latter negative. Furthermore, the NGS analysis revealed slight and dynamic changes of mutational profiles between different metastatic lesions, potentially impacting breast cancer management and prognosis. These alterations may reflect tissular and temporal changes in tumour subclones and may also be due to the selective pressure caused by antineoplastic treatment. The use of genomic analyses in order to improve cancer treatment has been studied prospectively with encouraging results. The widespread use of NGS tests in clinical practice also creates new challenges. The most relevant may be to know which genomic alterations detected should be valued and how they should be targeted.

Circulating low density neutrophils of breast cancer patients are associated with their worse prognosis due to the impairment of T cell responses.

Neutrophils are prominent immune components of tumors, having either anti-tumor (N1) or pro-tumor activity (N2). Circulating neutrophils, divided into high density neutrophils (HDN) and low density neutrophils (LDN), functionally mirror those N1 and N2 cells, respectively. LDN are rare in non-pathological conditions, but frequent in cancer, exhibiting a pro-tumor phenotype. These findings have been mainly demonstrated in animal models, thus proper validation in humans is still imperative. Here, we observed that LDN were increased in the blood of breast cancer (BC) patients, particularly with metastatic disease. Within the population of non-metastatic patients, LDN were more prevalent in patients with poor response to neoadjuvant chemotherapy than patients with a good response. The higher incidence of LDN in BC patients with severe disease or resistance to treatment can be explained by their pro-tumor/immunosuppressive characteristics. Moreover, the percentage of LDN in BC patients' blood was negatively correlated with activated cytotoxic T lymphocytes and positively correlated with immunosuppressive regulatory T cells. The ability of LDN to spoil anti-tumor immune responses was further demonstrated ex vivo. Hence, this study reveals the potential of LDN as a biomarker of BC response to treatment and opens new avenues for developing new immunotherapies.

Human Microbiota and Immunotherapy in Breast Cancer - A Review of Recent Developments.

Breast cancer (BC) is the most common malignancy and the second cause of cancer-specific death in women from high-income countries. Infectious agents are the third most important risk factor for cancer incidence after tobacco and obesity. Dysbiosis emerged as a key player that may influence cancer development, treatment, and prognosis through diverse biological processes. Metastatic BC has a highly variable clinical course, and more recently, immune checkpoint inhibitors (ICIs) have become an emerging therapy in BC. Even with standardised treatment protocols, patients do not respond similarly, reflecting each individual´s heterogeneity, unique BC features, and tumour microenvironment. However, there is insufficient data regarding predictive factors of response to available treatments for BC. The microbiota could be a crucial piece of the puzzle to anticipate better individual BC risk and prognosis, pharmacokinetics, pharmacodynamics, and clinical efficacy. In recent years, it has been shown that gut microbiota may modulate cancer treatments' efficacy and adverse effects, and it is also apparent that both cancer itself and anticancer therapies interact with gut microbiota bidirectionally. Moreover, it has been proposed that certain gut microbes may protect the host against inappropriate inflammation and modulate the immune response. Future clinical research will determine if microbiota may be a prognostic and predictive factor of response to ICI and/or its side effects. Also, modulation of microbiota can be used to improve outcomes in BC patients. In this review, we discuss the potential implications of metabolomics and pharmacomicrobiomics that might impact BC immunotherapy treatment.

Expression of HLA-DR in Cytotoxic T Lymphocytes: A Validated Predictive Biomarker and a Potential Therapeutic Strategy in Breast Cancer.

Neoadjuvant chemotherapy (NACT) is common in breast cancer (BC) treatment, though more than half of the patients lack an effective response. Therefore, new predictive biomarkers and alternative therapies are crucial. Previously, we proposed HLA-DR-expressing cytotoxic T lymphocytes (CTLs) as a potential biomarker of the response to NACT. To validate this observation and further investigate these cells, 202 BC patients were enrolled. Flow cytometry analyses were performed in 61 biopsies and 41 blood samples pre-NACT and 100 non-NACT tumor samples. All the patients were followed up for 34 months. Blood-isolated immune cells were cultured with BC cell lines in a 3D system. We confirmed that HLA-DR level in CTLs is a highly sensitive, specific, and independent biomarker to predict response to NACT and developed a predictive probability model. This biomarker was also associated with progression-free survival, regardless of the treatment. The clinical observations are substantiated by the anti-tumor properties of HLA-DR-expressing CTLs. Intriguingly, HLA-DR level in CTLs can be modulated ex vivo, boosting their capacity to kill tumor cells synergistically with doxorubicin. Thus, HLA-DR expression in CTLs is a validated tool to select patients that will actually benefit from NACT, and its stimulation might be a novel therapeutic approach for BC.

Human Microbiota and Breast Cancer-Is There Any Relevant Link?-A Literature Review and New Horizons Toward Personalised Medicine.

Breast cancer (BC) is the most common malignancy and the second cause of cancer-specific death in women from high-income countries. Recently, gut microbiota dysbiosis emerged as a key player that may directly and/or indirectly influence development, treatment, and prognosis of BC through diverse biological processes: host cell proliferation and death, immune system function, chronic inflammation, oncogenic signalling, hormonal and detoxification pathways. Gut colonisation occurs during the prenatal period and is later diversified over distinct phases throughout life. In newly diagnosed postmenopausal BC patients, an altered faecal microbiota composition has been observed compared with healthy controls. Particularly, ß-glucuronidase bacteria seem to modulate the enterohepatic circulation of oestrogens and their resorption, increasing the risk of hormone-dependent BC. Moreover, active phytoestrogens, short-chain fatty acids, lithocholic acid, and cadaverine have been identified as bacterial metabolites influencing the risk and prognosis of BC. As in gut, links are also being made with local microbiota of tumoural and healthy breast tissues. In breast microbiota, different microbial signatures have been reported, with distinct patterns per stage and biological subtype. Total bacterial DNA load was lower in tumour tissue and advanced-stage BC when compared with healthy tissue and early stage BC, respectively. Hypothetically, these findings reflect local dysbiosis, potentially creating an environment that favours breast tumour carcinogenesis (oncogenic trigger), or the natural selection of microorganisms adapted to a specific microenvironment. In this review, we discuss the origin, composition, and dynamic evolution of human microbiota, the links between gut/breast microbiota and BC, and explore the potential implications of metabolomics and pharmacomicrobiomics that might impact BC development and treatment choices toward a more personalised medicine. Finally, we put in perspective the potential limitations and biases regarding the current microbiota research and provide new horizons for stronger accurate translational and clinical studies that are needed to better elucidate the complex network of interactions between host, microorganisms, and drugs in the field of BC.