Predictors of HER2 gene amplification in immunohistochemistry score 2+ Early Breast Cancer according to 2018 ASCO/CAP guidelines: a single institution analysis.

Background: HER2 overexpression occurs in approximately 15-20% of invasive breast cancers (BC). From a pathological point of view HER2 positivity is defined by intense circumferential membrane complete staining in more than 10% of tumour cells in immunohistochemistry (IHC score 3+). When complete circumferential staining is weak to moderate (IHC score 2+) double probe in situ ibridation (ISH) is mandatory to define HER2 status. In 2018 ASCO/CAP guidelines were updated to provide additional guidance in HER2 equivocal cases to allow a greater discrimination between positive and negative cases. Our aim is to find predictors of HER2 positivity among IHC score 2+ early breast cancer specimens analysed according to 2018 ASCO/CAP guidelines. Patients and methods: 253 cases of early BC diagnosed at Modena Cancer Center between November 2013 and August 2017 were identified. Stage, ISH result, hormonal receptor status (HR), proliferation index (MIB1), and histological grade were captured; menopausal status was available too. All IHC score 2+ cases were reclassified according to 2018 ASCO/CAP guidelines. The association between pathological tumour features, clinical characteristics and ISH positivity was assessed using Fisher test. Results: Overall, 25.7% IHC score 2+ BC resulted HER2 amplified in double probe ISH. High tumour grade (G3 vs G1-2) and MIB1 > 20% significantly predict HER2 ISH amplification (p=0,0001). No correlation was found according to HR, stage, or menopausal status. The majority (185; 98.4%) of HER2-ve BC were reclassified as group 5 (HER2/ CEP17 ratio <2 and HER2 copy number <4 signals/cell) except for 3 specimens classified as group 4 (HER2/CEP17 RATIO <2 and HER2 copy number \ub34 but <6 signals/cell). In HER2+ve group the majority (62; 95.3%) specimens were group 1 (HER2/CEP17 RATIO >2 and HER2 copy number =4 signals/cell), no specimen was group 2, and only 3 cases were classified as group 3 (HER2/CEP17 RATIO <2 and HER2 copy number >6 signals/cell). Conclusions: In this IHC score 2+ BC series, reclassification according to 2018 ASCO/CAP guidelines identified only 4.6% group 3 and 1.6% group 4 cases. The routinely assessment of grading and proliferation index could help to predict HER2 amplification in IHC score 2+ samples even if it must not substitute ISH assay in determining eligibility for HER2 targeted therapies

Quality of life of therapies for hormone receptor positive advanced/metastatic breast cancer: Regulatory aspects and clinical impact in Europe

In recent years, the number of trials incorporating health-related quality of life (HRQoL) data has increased. The impact of HRQoL on regulatory decision making in the European context and on clinical practice is not well established. We conducted an analysis of the role of QoL data extracted from the clinical trials of the drugs approved for hormone receptor positive/HER2-negative advanced/metastatic breast cancer (mBC). The results from the HRQoL were collected and a meta-analysis was performed to evaluate the impact of experimental drugs compared to standard treatments. The results showed a non-detrimental effect in HRQoL from the new treatments. As regards the approval process, from an examination of the European Medicine Agency (EMA) documents, HRQoL was reported nonextensively and contained and discussed in the European assessment reports (EPARs) for eleven trials in the approval process and cited in three cases in the EPARs and summary of medicinal product characteristics (SmPC). An effort should be made by all the stakeholders to increase the visibility of the HRQoL results in order to allow increased consideration in the approval process to make QoL data more easily and visibly available for the clinician and the patients. The evaluation should be reflected in the SmPC in order to increase the amount of information provided to the physician

Pre and post anti Her-2 therapy era: a mono-institutional analysis of the outcome in patients with residual disease after neoadjuvant therapy for Her-2 positive locally advanced breast cancer.

Background: Anti Her-2+ therapies (aH2Tx) have changed the outcome of women with Her2 positive (Her2+) breast cancer and its activity showed a considerable impact in the neoadjuvant setting in which a higher rate of pathologic complete response (pCR) was observed. Of interest is the difference in outcome of patients who did not achieved a pCR and the analysis of the residual disease (RD) represents a relevant issue to explore to identify the subset of patients ( pts) with different outcome. Methods: 67 consecutive Her-2+ pts with locally advanced breast cancer (LABC) treated since 1993 to 2015 and who did not reached a pCR were evaluated. A minimum of three years of follow up was requested for the outcome analysis. Overall survival (OS) and disease free survival (DFS) has been explored in the two cohorts and the type of RD after neoadjuvant aH2Tx was also examined. Immunochemistry expression for estrogen and progesterone receptors (ER/PR) in the primary tumor for the aH2Tx-not-receiving pts was: 8 pts was ER/PR negative, 10 were ER/PR positive, 6 were ER-/PR + , 1 ER + /PR-. In the aH2Tx-receiving group: 26 were ER/PR + , 6 were ER + /PR-, 10 were ER/PR negative. Results: 25 pts did not receive aH2Tx in the neoadjuvant and 19 did not in adjuvant setting. 42 pts received aH2Tx in the neoadjuvant and 35 also in the adjuvant setting. Eleven pts in the aH2Tx-non-receiving group had recurrent disease compared with five recurrences in the aH2Tx-receiving group. The subtypes of RD in the aH2Tx not-receiving group were as follow: 4 had Luminal A like disease, 2 Luminal B like, 1 was triple negative, 18 were Her2+. For the aH2Tx-receiving group: 4 were Luminal A like, 5 Luminal B like, 30 were Her2+. The subtype of RD in the aH2Tx-not-receiving group with recurrent disease it has changed in 2 out of 11 pts if compared to primary tumor and in 2 out of 5 pts of the aH2Tx-receiving group. Conclusion: Recurrent disease was observed more often in the non-receiving aH2Tx pts, the analysis of impact of RD on outcome is still pending and will be presented at the meeting. Optimizing the selection of aH2Tx by identifying subpopulations of Her-2+ pts who need more or less therapy could be cost effective and would spare some patients unnecessary exposure to ineffective treatments

Role of Intrinsic Subtype Analysis with PAM50 in Hormone Receptors Positive HER2 Negative Metastatic Breast Cancer: A Systematic Review.

Endocrine therapy (ET), associated with CDK 4/6 inhibitors, represents the first choice of treatment for HR+/HER2- metastatic breast cancer (mBC). Primary or secondary endocrine resistance could develop; however validated biomarkers capable of predicting such a conditions are not available. Several studies have shown that HR+/HER2- mBC comprises five intrinsic subtypes. The purpose of this systematic review was to analyze the potential correlations between intrinsic subtype, efficacy of treatment, and patient outcome. Five papers that analyzed the intrinsic subtype with PAM50 assay in patients (pts) with HR+/HER2- mBC treated with ET (alone or in combination) within seven phase III clinical trials (EGF30008, BOLERO-2, PALOMA-2,3, MONALEESA-2,3,7) were identified. Non-luminal subtypes are more frequent in endocrine-resistant pts and in metastatic sites (vs. primary tumors), have less benefit from ET, and worse prognosis. Among these, HER2-enriched subtypes are similar to HER2+ tumors and benefit from the addition of anti-HER2 agents (lapatinib) and, for less clear reasons, of ribociclib (unconfirmed data for palbociclib and everolimus). Basal-like subtypes are similar to triple-negative tumors, making them more sensitive to chemotherapy. The intrinsic subtype is also not static but can vary over time with the evolution of the disease. Currently, the intrinsic subtype does not play a decisive role in the choice of treatment in clinical practice, but has potential prognostic and predictive value that should be further investigated

T-DM1 efficacy in trastuzumab-pertuzumab pre-treated HER2 positive metastatic breast cancer patients: a meta-analysis.

Background: Current guidelines consider T-DM1 the standard 2nd line therapy for HER2 positive metastatic breast cancer (MBC) patients following trastuzumab (T) + pertuzumab (P) and taxane 1st line treatment. Despite this, there are no prospective studies supporting this sequence. Methods: We performed a meta-analysis using real world data to determine the efficacy of T-DM1 after 1st line TP in HER2 positive MBC patients. We used a random-effect model to find differences in the rate of 1-year progression free survival (PFS) between TP pre-treated population and the EMILIA phase III pivotal trial. Results: Seven studies were eligible. The meta-analysis showed a combined 1-year PFS risk difference for T-DM1 efficacy after TP in 2nd or more lines of -0.122, with lower and upper limits of -0.253 and 0.010, respectively (p = 0.07), with low heterogeneity among studies (I2 0.01%, p = 0.836). Considering the four studies on T-DM1 in 2nd line setting, 1-year PFS risk was -0.034 (95% CI -0.207 - 0,139; p = 0.701) (I2 0.01%, p = 0.91). Conclusion: Overall, the efficacy of T-DM1 after TP seems to be similar to that previously reported in the EMILIA trial. In the second line setting, data are not mature enough to confirm T-DM1 efficacy in TP pre-treated population

Impact of time to surgery after neoadjuvant chemotherapy in patients with operable breast cancer.

Background: Some studies of adjuvant chemotherapy (CT) suggested that a shorter interval before the start of therapies may improve survival outcomes in many groups of patients. Time to surgery (TTS) after neoadjuvant CT and survival outcomes have not been established yet. The aim of this study is to evaluate the impact of TTS after neoadjuvant CT in terms of Overall Survival (OS) and Disease Free Survival (DFS). Patients and Methods: A retrospective analysis was conducted in 295 patients receiving neoadjuvant CT for stage I-IIIc breast cancer between 1991 and 2013. 56 pts underwent surgery within 21 days (group A) from last CT cycle, 148 pts within 22-35 days (group B) and 91 pts after 36 days (group C). The majority were infiltrating ductal carcinoma, stage IIA (37.6%) and IIB (33.9%), with nodal involvement in 51.6% of the cases. LumA 18.3%, LumB/HER2- 28.2%, LumB/Her2+ 20.7%, HER2+ 9.8%, TNBC 21%. All patients were treated with neoadjuvant CT: 70.5% with anthra-taxanes based regimen, 18% with anthra- alone, 10.9% with taxanes alone, 0.3% with CMF; plus Trastuzumab in 70% of HER2+ diseases. Results: After a median follow up of 4.6 years, it was observed that patients in group A showed a significant better OS than group B (HR 4.22; 95% CI, 1.27 \u2013 14.00, p=0.018) and group C (HR 3.61; 95% CI, 1.01 \u2013 12.86, p=0.048). Moreover group A showed a significant better DFS than group B (HR 3.41; 95% CI 1.34 to 8.65, p=0.010) and group C (HR 3.77; 95% CI 1.42 to 9.95, p=0.007). No correlations with OS were found in pts who achieved pCR (20.7%); pCR was predictive of better 5- and 10-years DFS independently from TTS (95.4% in the pCR-group vs 75.4% of non-pCR group, HR 0.16; 95% CI 0.04 to 0.66, p=0.011). TTS may influence DFS in non-pCR group: indeed 5-years DFS is 97.3% in group A, 72.7% in group B (HR 2.89; 95% CI 1.14 to 7.36, p=0.026), and 68.5% in group C (HR 3.44; 95% CI 1.3 to 9.1, p=0.013). No significant correlations with regard of stage at diagnosis or molecular subtypes were found. Conclusions: These results suggest that TTS after primary CT may influence patients' survival, regardless of stage at diagnosis and tumor subtype, so that a shorter interval between that last cycle of neoadjuvant chemotherapy and breast surgery should be addressed whenever possible

Endocrine therapy alone versus targeted combination strategy as first line treatment in elderly patients with hormone receptor-positive advanced breast cancer: Meta-analysis of phase II and III randomized clinical trial

Background Combined endocrine/targeted approaches have been investigated as first-line treatment in hormone receptors positive metastatic breast cancer (BC). Randomized trials showed that the addiction of CDK (cyclin-dependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged >65 years) are under represented in most of the trials. Due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present meta-analysis aimed to understand the role of the new endocrine approaches in elderly women. Methods This meta-analysis included first line phase II/III randomized published trials comparing ET to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged > 65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Prospero registration number: CRD42019120215. Results 8 studies were included: 4 (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found. Conclusions The novel experimental strategies showed an improvement in PFS in elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone, the magnitude of PFS benefit is age-independent. To define the role of novel agents, future trials should be designed taking in account not only the age, but also adequate geriatric assessment and comorbidity status

erbb2 and pi3kca mutations in endocrine resistant breast cancer bc

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Efectividad del aceite esencial de orégano mexicano de República Dominicana (Lippia graveolens) contra plagas del maíz (Sitophilus zeamais y Fusarium verticillioides)

The insecticidal and antifungal properties of Mexican oregano (Lippia graveolens) essential oil from the Dominican Republic were investigated under laboratory conditions against two main pests of stored grains: Sitophilus zeamais and Fusarium verticillioides. Although oregano essential oil at 600 ?l/l air did not result in a significant mortality of S. zeamais after 24 hours of exposure by fumigation, this essential oil was a powerful acetylcholinesterase (AChE) inhibitor in vitro. One of the main components of oregano essential oil, p-cymene, presented fumigant toxicity and AChE inhibition activity against the maize weevil. The L. graveolens essential oil antifungal activity against F. verticillioides was evaluated at 50, 100 and 200 ?l/l, and it was found that growth parameters were affected by the presence of oregano essential oil in the media, whereas FB1 production was not inhibited. The results demonstrate that oregano essential oil and p-cymene can be used as alternatives to synthetic pesticides against F. verticillioides and S. zeamais, respectively.Se estudiaron en condiciones de laboratorio las propiedades insecticidas y fungicidas del aceite esencial de orégano mexicano (Lippia graveolens) de República Dominicana contra dos plagas principales de granos almacenados: Sitophilus zeamais y Fusarium verticillioides. Aunque el aceite esencial de orégano a 600 ?l/l de aire no resultó en una mortalidad significativa de S. zeamais después de 24 horas de exposición a la fumigación, fue un potente inhibidor de la acetilcolinesterasa (AChE) in vitro. El p-cimeno, uno de los principales componentes del aceite esencial, presentó actividad fumigante y de inhibición de la AChE contra el gorgojo del maíz. Además se evaluó la actividad antifúngica frente a F. verticillioides a 50, 100 y 200 ?l/l y se encontró que los parámetros de crecimiento del hongo fueron afectados por la presencia del aceite esencial de orégano en el medio, mientras que la producción de fumonisina B1 (FB1) no se inhibió. Los resultados demuestran que el aceite esencial de orégano y el p-cimeno se pueden usar como alternativas a los pesticidas sintéticos contra F. verticillioides y S. zeamais, respectivamente

Targeting PI3K/AKT/mTOR Pathway in Breast Cancer: From Biology to Clinical Challenges

Breast cancer (BC) is the most common women cancer and cause of cancer death. Despite decades of scientific progress in BC treatments, the clinical benefit of new drugs is modest in several cases. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway mutations are frequent in BC (20-40%) and are significant causes of aggressive tumor behavior, as well as treatment resistance. Improving knowledge of the PI3K/AKT/mTOR pathway is an urgent need. This review aims to highlight the central role of PI3K-mTORC1/C2 mutations in the different BC subtypes, in terms of clinical outcomes and treatment efficacy. The broad base of knowledge in tumor biology is a key point for personalized BC therapy in the precision medicine era