Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study.

BACKGROUND: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. METHODS: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05. RESULTS: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS. CONCLUSIONS: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

Unfolding the role of the PI3K/AKT/MTOR pathway in male breast cancer: A pragmatic appraisal.

Breast cancer in men is rare, but a relevant public health issue, yielding a 25% higher risk of mortality comparing to female counterparts. The representation of males in clinical trials has been scarce and treatment decisions are based mainly on extrapolations from data in females. In the setting of estrogen-dependent metastatic disease, the use of everolimus has been seldom reported, although the PI3K/AKT/mTOR pathway seems to be a critical oncogenic driver. This paper dissects hallmark biological features of ER+/HER2-advanced male breast cancer, setting a comprehensive basis to promote personalized care, focusing on the potential of targeting the PI3K/AKT/mTOR pathway.

Prognostic Impact of Type 2 Diabetes in Metastatic Colorectal Cancer.

Background Diabetes mellitus (DM) is a prognostic factor for some malignancies, but its clinical implications in metastatic colorectal cancer (mCRC) patients are less clear. Therefore, we conducted a retrospective study to evaluate the impact of pre-existing type 2 diabetes mellitus (T2DM) on the survival outcomes of patients with newly diagnosed mCRC. Methodology We retrospectively included patients with newly diagnosed mCRC between January 2017 and June 2021 and with pre-existing T2DM. Data on the characteristics of patients, clinicopathological features, and drug exposure were collected from the electronic medical records. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS) and treatment-related adverse events (TRAEs). Results Among 187 mCRC patients, 54 (28.8%) had T2DM. The median follow-up was 25 months. We observed 150 OS events and 168 PFS events. Diabetes significantly and negatively impacted PFS and OS. The median for PFS (mPFS) was eight and 16 months for T2DM and no T2DM patients, respectively (p < 0.0001; log-rank test). The median overall survival (mOS) was 15 and 29 months for T2DM and no T2DM patients, respectively (p < 0.0001; log-rank test). Patients with diabetes were more often overweight or obese (59.3% vs. 24.8%; p < 0.01) and had a poorer performance status (53.7% vs. 21.1% with Eastern Cooperative Oncology Group Performance Status 1; p < 0.01). Additionally, T2DM patients had more high-risk pathological features, including G3 grading tumors (27.7% vs. 12.0%; p = 0.01), lymph node involvement (p < 0.01), BRAF-mutated (35.1% vs. 6.8%; p < 0.01), and right-sided CRC (63.0% vs. 30.1%; p < 0.01). We found no statistically significant differences in TRAEs. Nevertheless, a significantly higher rate of grade 2-4 peripheral neuropathy (22.2% vs. 5.3%; p < 0.01) was reported in T2DM patients. Conclusions T2DM is a negative prognostic factor for survival in mCRC. The paper provides empirical evidence in favor of the joint control of both pathologies. Further research is needed to establish the robustness of our results.

Impact of Human Epidermal Growth Factor Receptor 2 (HER2) Low Status in Response to Neoadjuvant Chemotherapy in Early Breast Cancer.

Introduction In clinical practice, there is a binary distinction between human epidermal growth factor receptor 2 (HER2)-positive and HER2-negative (HER2-) breast cancer (BC). However, within HER2- disease, there is significant heterogeneity. Particularly, HER2- tumors that express some level of HER2 by immunohistochemistry (IHC) score 1+ or 2+/in situ hybridization (ISH) non-amplified are currently defined as HER2-low. This subgroup has shown distinct biological features compared to HER2-zero (HER2-0) BC and additionally novel antibody-drug conjugate therapies have demonstrated a potential and promising activity in HER2-low BC population. This study aims to evaluate the impact of HER2-low status in response to neoadjuvant chemotherapy (NACT) in HER2- BC being HER2-low and HER2-0 status. Materials and methods In a single institution, we retrospectively reviewed clinical and pathological data of HER2 early-stage BC patients treated with NACT following definitive surgery from January 2015 to December 2020. Tumors with HER2 IHC 0 were classified as HER2-0 and IHC score 1+ and 2+/ISH non-amplified as HER2-low. The primary objective was to evaluate the rate of pathological complete response (pCR) using the definition of ypT0/Tis ypN0 according to HER2-low and HER2-0 subgroups. Secondary objectives were to evaluate biological features between the two subgroups, disease-free survival (DFS), and overall survival (OS). Pearson chi-square, Fisher's exact, and Mann-Whitney tests were performed. The Kaplan-Meier method was used to plot DFS and OS curves. A p-value of <0.05 was considered statistically significant. Results A total of 72 patients with HER2 BC were included with a median age at diagnosis of 52.5 years and a median follow-up time of 35.5 months. Of patients, 56.9% had HER2-low disease and 43.1% had HER2-0 disease. Significant differences between the two subgroups were detected regarding hormonal receptor status and proliferation grade (Ki67). In the HER2-low subgroup, 70% of tumors were luminal-like and 64.5% of HER2-0 patients had triple-negative BC (p = 0.03). There were statistically significant differences regarding estrogen (p = 0.00) and progesterone (p = 0.02) receptors. The median Ki67 rate was higher in the HER2-0 subset (mean rank = 43.9) compared to HER2-low (mean rank = 30.9) and this difference was statistically significant (p = 0.00). HER2-low patients presented more stage III tumors (65.9%) and HER2-0 patients were mainly stage II (61.3%), and this was statistically relevant (p = 0.03). The prevalence of other clinical and pathological features was comparable between both groups. HER2-low subgroup achieved lower pCR rates (14.6% vs. 29.0%) but this difference was not statistically significant (p = 0.15). Similarly, there was no difference between the two subgroups regarding DFS (p = 0.97) and OS (p = 0.35), although the data were immature. Conclusion As in prior studies, this study did not support a significant impact of HER2-low status on response to NACT in HER2- patients with early-stage BC. HER2-low patients had a lower pCR, which may suggest a worse response to classic chemotherapy regimen and may have clinical implications that should be further exploited. The prevalence of hormonal receptors in HER2-low tumors was consistent with previous data in the literature. Although retrospective, the data suggest that HER2-low tumors should be regarded as a distinct biological subtype and more research is warranted.

Association of Weight Change, Inflammation Markers and Disease Staging with Survival of Patients Undergoing Chemotherapy for Pancreatic Adenocarcinoma.

INTRODUCTION: Cancer-associated-cachexia represents a systemic syndrome of unintended weight-loss (WL) and systemic inflammation, affecting >80% patients with pancreatic adenocarcinoma (PA). We aimed to evaluate the association of weight change (WC) with survival of patients treated with chemotherapy (ChT) for PA and the influence of disease staging. We also studied the prognostic and predictive value of inflammation-based scores. METHODS: Observational, retrospective cohort study. Individuals were divided into two cohorts, according to WC (WL ≥5% vs. non-WL <5%) after ChT. Main endpoints were weight change and survival time. Statistical analysis was performed using Stata software. RESULTS: Sixty-five patients were included (median age 69; 48% female), 60% with advanced disease. At 3 months after ChT start, 54% experienced WL. Advanced disease independently predicted WL (OR 2.10; 95% CI, 1.11-19.6; p = 0.041). With median follow-up of 14.8 mo, median survival time of patients with WL was 18.5 mo, vs. 33.2 vs. for non-WL (HR 2.28; 95% CI, 1.15-4.52; p = 0.019). In patients with early-stage disease, WL was associated with decreased survival time (21.9 vs. 67.6 mo; HR 23.68; 95% CI 2.39-234.75; p = 0.007), while the association of WL on survival time in advanced disease was not significant (HR 0.74; 95% CI, 0.34-1.60; p = 0.449). The multivariate survival model showed that WL (HR 1.11, 95% CI 1.03-1.20, p = 0.005) and cachexia (HR 3.76, 95% CI 1.07-13-18), p = 0.041) were associated with survival time, as well as location in body or tail (HR 3.05; 95% CI, 1.75-5.31; p < 0.001) and high Neutrophil-to-lymphocyte ratio (NLR) at 3 months (HR 6.20; 95% CI, 2.59-14.87; p < 0.001). CONCLUSION: WL was an independent prognostic factor for survival. Particularly in early stage disease, interventions targeting this modifiable factor may translate into better outcomes for PA patients. NLR may be a surrogate marker of systemic inflammatory status in this setting.

Therapeutic Futility in Terminal Cancer Patients: A Retrospective and Observational Study.

Introduction Advanced cancer patients often need therapy for symptomatic control, in addition to cancer and other disease treatments. As the cancer disease progresses and life expectancy decreases, there should be a change in the goal of care. If this change is not accompanied by therapeutic adjustments, there is a risk of maintaining useless and ineffective treatments, as well as potential harmful drug interactions. This study analyzed the prevalence of therapeutic futility in patients with advanced cancer disease. Materials and methods This was a retrospective and observational single-center study, that included advanced cancer patients who died during the hospital stay, at a University Hospital in Lisbon, Portugal. Demographic and clinical data were collected. A Palliative Prognostic Score (PaP) was used to stratify patients according to their prognosis group. An analysis of the prescribed therapy was performed to quantify the "potentially inappropriate medications" (PIMs) and "inappropriate medications" (IMs), at admission and 24 hours prior to the patient's death. Results Over 140 patients were included. On the first day of hospitalization, 119 patients (85%) were exposed to at least one IM or PIM and 100 patients (71%) were still exposed to at least one IM or PIM in the last 24 hours of life. Regarding chemotherapy, 66 patients (47%) had treatment in the last two months of life, 38 (27%) in the last month, and 17 (12%) in the last two weeks prior to death. Therapeutic simplification (suspension of IMs and reduction of at least 50% of PIMs during hospitalization) was performed in 43% of the overall population and was higher in PaP score group C, but not statistically significant (p=0.09). The patient's inclusion in PaP score group C and inpatient consultation by the palliative care team were independent predictors of therapeutic simplification. Discussion There is an effort to achieve greater therapeutic suitability in palliative patients. However, many patients maintain futile and disproportionate therapy at the end of life (EoL). In many cases, systemic cancer treatment is performed until quite late in the course of the disease. The prescription of PIMs was significantly higher than that of IMs, which could be expected given their definition. A shorter life expectancy at admission led to a greater therapeutic simplification, as well as an intervention by the Palliative Care Team, which can be explained by the more focused approach towards quality-of-life improvement and symptomatic control. Different than expected the prescription of supportive therapies at hospital admission was not a predictor of therapeutic simplification. Although there was a reduction in IMs and PIMs in the studied population, and therapeutic simplification occurred in one fraction of the patients, the fact is that more than half of the patients evaluated did not undergo therapeutic simplification as defined in this work. Conclusion It appears that there is an effort to achieve greater therapeutic suitability in palliative patients, however, many patients maintain futile therapy at the EoL. It is of paramount importance to change the standard of care in this setting, to privilege a more patient-focused approach and tailored therapy, and to prioritize symptomatic control and quality-of-life improvement.

From Theory to Practice: Bone Health in Women with Early Breast Cancer Treated with Aromatase Inhibitors.

Aromatase inhibitors (AI) are extensively used as adjuvant endocrine therapy in post-menopausal women with hormone receptor-positive early breast cancer (HR+ EBC), but their impact on bone health is not negligible. This work aimed to assess bone loss, fracture incidence, and risk factors associated with these events, as well as the prognostic influence of fractures. We have conducted a retrospective cohort study of women with HR+ EBC under adjuvant therapy with AI, during a 3-year period. Four-hundred-and-fifty-one eligible women were reviewed (median age 68 years). Median time under AI was 40 months. A fracture event occurred in 8.4%, mostly in the radium and femoral neck and in older women (mean 74 vs. 68 years, p = 0.006). Age (OR 1.01, 95% CI 1.01-1.07, p = 0.024) and time under AI (OR 1.02, 95% CI 1.00-1.04, p = 0.037) were independent predictors of fracture, with a fair discrimination (AUC 0.71). Analysis of disease-free survival according to fracture event varied between groups, disfavoring the fracture cohort (at 73 months, survival 78.6%, 95% CI, 47.6-92.4 vs. 95.6%, 95% CI, 91.2-97.8, p = 0.027). The multivariate model confirmed the prognostic impact of fracture occurrence (adjusted HR of 3.17, 95% CI 1.10-9.11; p = 0.032). Bone health is often forgotten, despite its great impact in survivorship. Our results validate the pathophysiologic link between EBC and bone metabolism, which translates into EBC recurrence. Further research in this area may help refine these findings. Moreover, early identification of women at higher risk for fractures is warranted.

Challenges and Considerations on Risk-Reducing Surgery in BRCA1/2 Patients with Advanced Breast Cancer.

Cancer survivors harboring inherited pathogenic variants in the breast cancer (BC) susceptibility genes BRCA1 or BRCA2 are at increased risk of ovarian cancer (OC) and also of contralateral BC. For these women, risk-reducing surgery (RRS) may contribute to risk management. However, women with locally advanced or metastatic breast cancer (ABC) were excluded from clinical trials evaluating the benefit of these procedures in the BRCA1/2 carriers, and thus, current guidelines do not recommend RRS in this specific setting. Although ABC remains an incurable disease, recent advances in treatment have led to increased survival, which, together with improvement in RRS techniques, raise questions about the potential role of RRS in the management of BRCA1/2 ABC patients. When should RRS be discussed as an option for BRCA1/2 patients diagnosed with ABC? To address this issue, we report two clinical cases that reflect new challenges in routine oncology practice. Team experience and patient motivations may shape multidisciplinary decisions in the absence of evidence-based data. A wise rationale may be the analysis of the competing risks of death by a previous ABC against risk of death by a secondary BC or OC, tailored to patient preferences.

Liquid Biopsies in Progressing Metastatic Colorectal Cancer- Application and their Therapeutic Implications According to the RAS Status.

Introduction The treatment of metastatic colorectal cancer (mCRC) now includes therapy with biological agents inthe first line of treatment. The advances of our knowledge in molecular biology of these tumors allowed the identification of signaling pathways involved in tumorigenesis as potential therapeutic targets. In this field, monoclonal antibodies against epidermal growth factor receptor (anti-EGFR) added to a chemotherapy doublet have demonstrated improved overall survival for these patients. However, mutations in oncogenes NRAS/KRAS are predictive of absence of response to these treatments. Therefore, genotyping in mCRC is essential to personalized treatment. It is known that tumoral heterogeneity and selective pression by targeted therapies can lead to changes in RAS mutational status, along the course of the disease. This opens the possibility of different targeted therapies. Tumor analysis through liquid biopsies allows for the detection of genetic alterations in a less invasive way than common solid tumor biopsy and is currently being validated in different settings, with promising results in mCRC. The main goal of this study was to assess therapeutic implications of Liquid Biopsy (LB) in treatment of progressive mCRC and its potential impact on survival.  Material and methods A retrospective, observational, unicentric study of patients diagnosed with progressive mCRC and who underwent LB after several lines of treatment, was performed. Analysis of patient and tumor characteristics, as well as LB results was performed with descriptive statistics and survival analysis according to Kaplan-Meier methods and COX analysis with STATA/IC software.  Results We included 18 patients on whom LB were performed (median age 61 years; 55% (n=10) men). The median follow-up was 37.4 months. At diagnosis, 12 patients had a KRAS mutation. In the LB reassessment, there was a change in the RAS status in six patients, who initially had a mutation and later showed KRASwt (wild type RAS). LB led to a change in the therapeutic plan in these six patients, allowing the use of anti-EGFR therapy. Progression Free Survival (PFS) and Overall Survival (OS) could not be calculated at this time. Conclusion LB can revolutionize the approach to mCRC by optimizing therapeutic sequencing in a continuum of care strategy. The search for genetic changes over the course of the disease allows a better therapeutic approach to each patient. In the study presented, the realization of LB allowed an increase in therapeutic options in 1/3 of the patients. It is important to continue these studies with larger samples in order to better validate this strategy.