Can cyclin-dependent kinase 4/6 inhibitors convert inoperable breast cancer relapse to operability? A case report

BACKGROUND Pathological complete response (pCR) is rare in hormone receptor-positive (HR+) HER2-negative breast cancer (BC) treated with either endocrine therapy (ET) or chemotherapy. Radical resection of locoregional relapse, although potentially curative in some cases, is challenging when the tumor invades critical structures. The oral cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with ET has obtained a significant increase in objective response rates and progression-free survival in patients with advanced BC and is now being evaluated in the neoadjuvant setting. We present a clinical case of a patient with an inoperable locoregional relapse of HR+ HER2-negative BC who experienced pCR after treatment with palbociclib.CASE SUMMARY We report the clinical case of a 60-year-old patient who presented with an inoperable locoregional relapse of HR+, HER2-negative BC 10 years after the diagnosis of the primary tumor. During a routine follow-up visit, breast magnetic resonance imaging and positron emission tomography/computed tomography revealed a 4-cm lesion in the right subclavicular region, infiltrating the chest wall and extending to the subclavian vessels, but without bone or visceral involvement. Treatment was begun with palbociclib plus letrozole, converting the disease to operability over a period of 6 mo. Surgery was performed and a pCR achieved. Of note, during treatment the patient experienced a very uncommon toxicity characterized by burning tongue and glossodynia associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. A reduction in the dose of palbociclib did not provide relief and treatment with the inhibitor was thus discontinued, resolving the tongue symptoms. Laboratory exams were unremarkable. Given that this was a late relapse, the tumor was classified as endocrine-sensitive, a condition associated with high sensitivity to palbociclib.CONCLUSION This case highlights the potential of the cyclin-dependent kinase 4/6 inhibitor plus ET combination to achieve pCR in locoregional relapse of BC, enabling surgical resection of a lesion initially considered inoperable

Cell-Free DNA Variant Sequencing Using CTC-Depleted Blood for Comprehensive Liquid Biopsy Testing in Metastatic Breast Cancer

Keup and colleagues provide liquid biopsy preliminary results by sequencing variants in circulating tumor cells (CTCs) and cell-free deoxyribonucleic acid (cfDNA) "all from one tube" format, in order to use the same blood sample under the same isolation conditions of both analytes to reach an unbiased comparability and consistency. We appreciated the attempt of the authors to improve technical procedures in liquid biopsy research area, but we wanted to raise several issues related to cfDNA detection, reporting our research experience. This is a feasibility study as the authors analyzed only one sample from a small case series at an advanced line of treatment. In the clinical practice to monitor the disease and predict the treatment response, the analysis should be done at multiple time points. We have previously demonstrated that the quantity and the integrity of the cfDNA are not useful to determine the evolution of early breast cancer (bc), maybe due to the fact that cfDNA is not strictly related to cancer but also to an inflammatory status. Given that a high content of cfDNA could reflect inflammatory processes, we decided to investigate the role of stimulator of interferon gene (STING), an important regulator of cancer cell growth and senescence, in bc tissue in relation to cfDNA. STING biomarker analyzed by immunohistochemistry on tumor tissue could reflect a circulating inflammatory status and needs to be further investigated, not only on CTCs but also on cfDNA. One of the major issues of cfDNA is to decide what to analyze on it, in terms of type of cells and genetic alterations. Considering that multiple tests could be done to study gene copy number alterations, mutations, and variant fusions, the proper molecular test should be chosen, on the basis of the clinical need, starting from the treatment choice to disease monitoring

Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. We analysed PKD1 and PKD2, in a large cohort of 440 unrelated Italian patients with ADPKD and 203 relatives by direct sequencing and MLPA. Molecular and detailed phenotypic data have been collected and submitted to the PKD1/PKD2 LOVD database. This is the first large retrospective study in Italian patients, describing 701 variants, 249 (35.5%) already associated with ADPKD and 452 (64.5%) novel. According to the criteria adopted, the overall detection rate was 80% (352/440). Novel variants with uncertain significance were found in 14% of patients. Among patients with pathogenic variants, in 301 (85.5%) the disease is associated with PKD1, 196 (55.7%) truncating, 81 (23%) non truncating, 24 (6.8%) IF indels, and in 51 (14.5%) with PKD2. Our results outline the high allelic heterogeneity of variants, complicated by the presence of variants of uncertain significance as well as of multiple variants in the same subject. Classification of novel variants may be particularly cumbersome having an important impact on the genetic counselling. Our study confirms the importance to improve the assessment of variant pathogenicity for ADPKD; to this point databasing of both clinical and molecular data is crucial

Ki67 and PR in Patients Treated with CDK4/6 Inhibitors: A Real-World Experience

CDK4/6 inhibitors (CDK4/6i) are recommended in patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer (ABC). Up to now, no prognostic biomarkers have been identified in this setting. We retrospectively analyzed the expression of progesterone receptor (PR) and Ki67, assessed by immunohistochemistry, in 71 ABC patients treated with CDK4/6i and analyzed the impact of these markers on progression-free survival (PFS). The majority of patients 63/71 (88.7%) received palbociclib, 4 (5.6%) received ribociclib, and 4 (5.6%) received abemaciclib. A higher median value of Ki67 was observed in cases undergoing second-line treatment (p= 0.047), whereas the luminal B subtype was more prevalent (p= 0.005). In the univariate analysis of the first-line setting, luminal A subtype showed a trend towards a correlation with a longer PFS (p= 0.053). A higher continuous Ki67 value led to a significantly shorter PFS. When the interaction between pathological characteristics and line of treatment was considered, luminal B subtype showed a significantly (p= 0.043) worse outcome (Hazard Ratio (HR) 2.84; 1.03-7.82 95% Confidence Interval (CI)). PFS in patients undergoing endocrine therapy plus CDK4/6i was inversely correlated with Ki67 expression but not with PR, suggesting that tumor proliferation has a greater impact on cell cycle inhibitors combined with endocrine therapy than PR expression

Pregnancy after breast cancer: Are young patients willing to participate in clinical studies?

Young patients with breast cancer (BC) are often concerned about treatment-induced infertility and express maternity desire. Conception after BC does not seem to affect outcome, but information in estrogen-receptor positive (ER+) disease is not definitive. From September 2012-March 2013, 212 evaluable patients with ER+ early BC,37 years at diagnosis, from 5 regions (Europe/US/Canada/Middle-East/Australia) answered a survey about fertility concerns, maternity desire and interest in a study of endocrine therapy (ET) interruption to allow pregnancy. Overall, 37% of respondents were interested in the study; younger patients (≤30 years) reported higher interest (57%). Motivation in younger patients treated30 months was higher (83%) than in older women (14%), interest was independent of age in patients treated for ≤30 months. A prospective study in this patient population seems relevant and feasible. The International-Breast-Cancer-Study-Group (IBCSG), within the Breast-International-Group (BIG) - North-American-Breast-Cancer-Groups (NABCG) collaboration, is launching a study (POSITIVE) addressing ET interruption to allow pregnancy

Exploitation of large archives of ERS and ENVISAT C-band SAR data to characterize ground deformations

In the last few years, several advances have been made in the use of radar images to detect, map and monitor ground deformations. DInSAR (Differential Synthetic Aperture Radar Interferometry) and A-DInSAR/PSI (Advanced DInSAR/Persistent Scatterers Interferometry) technologies have been successfully applied in the study of deformation phenomena induced by, for example, active tectonics, volcanic activity, ground water exploitation, mining, and landslides, both at local and regional scales. In this paper, the existing European Space Agency (ESA) archives (acquired as part of the FP7-DORIS project), which were collected by the ERS-1/2 and ENVISAT satellites operating in the microwave C-band, were analyzed and exploited to understand the dynamics of landslide and subsidence phenomena. In particular, this paper presents the results obtained as part of the FP7-DORIS project to demonstrate that the full exploitation of very long deformation time series (more than 15 years) can play a key role in understanding the dynamics of natural and human-induced hazards. © 2013 by the authors

Predictors of Enhancing Human Physical Attractiveness: Data from 93 Countries

People across the world and throughout history have gone to great lengths to enhance their physical appearance. Evolutionary psychologists and ethologists have largely attempted to explain this phenomenon via mating preferences and strategies. Here, we test one of the most popular evolutionary hypotheses for beauty-enhancing behaviors, drawn from mating market and parasite stress perspectives, in a large cross-cultural sample. We also test hypotheses drawn from other influential and non-mutually exclusive theoretical frameworks, from biosocial role theory to a cultural media perspective. Survey data from 93,158 human participants across 93 countries provide evidence that behaviors such as applying makeup or using other cosmetics, hair grooming, clothing style, caring for body hygiene, and exercising or following a specific diet for the specific purpose of improving ones physical attractiveness, are universal. Indeed, 99% of participants reported spending \u3e10 min a day performing beauty-enhancing behaviors. The results largely support evolutionary hypotheses: more time was spent enhancing beauty by women (almost 4 h a day, on average) than by men (3.6 h a day), by the youngest participants (and contrary to predictions, also the oldest), by those with a relatively more severe history of infectious diseases, and by participants currently dating compared to those in established relationships. The strongest predictor of attractiveness-enhancing behaviors was social media usage. Other predictors, in order of effect size, included adhering to traditional gender roles, residing in countries with less gender equality, considering oneself as highly attractive or, conversely, highly unattractive, TV watching time, higher socioeconomic status, right-wing political beliefs, a lower level of education, and personal individualistic attitudes. This study provides novel insight into universal beauty-enhancing behaviors by unifying evolutionary theory with several other complementary perspectives

The role of immune suppression in COVID-19 hospitalization: clinical and epidemiological trends over three years of SARS-CoV-2 epidemic

Specific immune suppression types have been associated with a greater risk of severe COVID-19 disease and death. We analyzed data from patients >17 years that were hospitalized for COVID-19 at the “Fondazione IRCCS Ca′ Granda Ospedale Maggiore Policlinico” in Milan (Lombardy, Northern Italy). The study included 1727 SARS-CoV-2-positive patients (1,131 males, median age of 65 years) hospitalized between February 2020 and November 2022. Of these, 321 (18.6%, CI: 16.8–20.4%) had at least one condition defining immune suppression. Immune suppressed subjects were more likely to have other co-morbidities (80.4% vs. 69.8%, p < 0.001) and be vaccinated (37% vs. 12.7%, p < 0.001). We evaluated the contribution of immune suppression to hospitalization during the various stages of the epidemic and investigated whether immune suppression contributed to severe outcomes and death, also considering the vaccination status of the patients. The proportion of immune suppressed patients among all hospitalizations (initially stable at <20%) started to increase around December 2021, and remained high (30–50%). This change coincided with an increase in the proportions of older patients and patients with co-morbidities and with a decrease in the proportion of patients with severe outcomes. Vaccinated patients showed a lower proportion of severe outcomes; among non-vaccinated patients, severe outcomes were more common in immune suppressed individuals. Immune suppression was a significant predictor of severe outcomes, after adjusting for age, sex, co-morbidities, period of hospitalization, and vaccination status (OR: 1.64; 95% CI: 1.23–2.19), while vaccination was a protective factor (OR: 0.31; 95% IC: 0.20–0.47). However, after November 2021, differences in disease outcomes between vaccinated and non-vaccinated groups (for both immune suppressed and immune competent subjects) disappeared. Since December 2021, the spread of the less virulent Omicron variant and an overall higher level of induced and/or natural immunity likely contributed to the observed shift in hospitalized patient characteristics. Nonetheless, vaccination against SARS-CoV-2, likely in combination with naturally acquired immunity, effectively reduced severe outcomes in both immune competent (73.9% vs. 48.2%, p < 0.001) and immune suppressed (66.4% vs. 35.2%, p < 0.001) patients, confirming previous observations about the value of the vaccine in preventing serious disease