Neoadjuvant approach as a platform for treatment personalization: focus on HER2-positive and triple-negative breast cancer.

The neoadjuvant setting provides unquestionable clinical benefits for high-risk breast cancer (BC) patients, mainly in terms of expansion of locoregional treatment options and prognostic stratification. Additionally, it is also emerging as a strategical tool in the research field. In the present review, by focusing on HER2-positive and triple-negative subtypes, we examined the role of the neoadjuvant setting as a research platform to facilitate and rationalize the placement of escalation strategies, promote the adoption of biomarker-driven approaches for the investigation of de-escalated treatments, and foster the conduction of comprehensive translational analyses, thus ultimately aiming at pursuing treatment personalization. The solid prognostic role of pathologic complete response after neoadjuvant therapy, and its use as a surrogate endpoint to accelerate the drug approval process were discussed. In this context, available data on escalated treatment strategies capable of enhancing pathologic complete response (pCR) rate or improving prognosis of patients with residual disease (RD) after neoadjuvant treatment, were comprehensively reviewed. We also summarized evidence regarding the possibility of obtaining pCR with de-escalated strategies, with particular emphasis on the role of biomarker-driven approaches for patient selection. Pitfalls of the dichotomy of pCR/RD were also deepened, and data on alternative/complementary biomarkers with a possible clinical relevance in this regard were reviewed

Biomarkers for HER2-positive metastatic breast cancer: Beyond hormone receptors.

The overexpression of human epidermal growth factor receptor-2 (HER2) results in a biologically and clinically aggressive breast cancer (BC) subtype. Since the introduction of anti-HER2 targeted agents, survival rates of patients with HER2-positive metastatic BC have dramatically improved. Currently, although the treatment decision process in metastatic BC is primarily based on HER2 and hormone-receptor (HR) status, a rapidly growing body of data suggests that several other sources of biological heterogeneity may characterize HER2-positive metastatic BC. Moreover, pivotal clinical trials of new anti-HER2 antibody-drug conjugates showed encouraging results in HER2-low metastatic BC, thus leading to the possibility, in the near future, to expand the pool of patients suitable for HER2-targeted treatments. The present review summarizes and puts in perspective available evidence on biomarkers that hold the greatest promise to become potentially useful tools for optimizing HER2-positive metastatic BC patients' prognostic stratification and treatment in the next future. These biomarkers include HER2 levels and heterogeneity, HER3, intrinsic molecular subtypes by PAM50 analysis, DNA mutations, and immune-related factors. Molecular discordance between primary and metastatic tumors is also discussed

Rare breast cancer subtypes: Histological, molecular, and clinical peculiarities

Breast cancer encompasses a collection of different diseases characterized by different biological and pathological features, clinical presentation, response to treatments, clinical behavior, and outcome. On the basis of cell morphology, growth, and architecture patterns, breast cancer can be classified in up to 21 distinct histological types. Breast cancer special types, including the classic lobular invasive carcinoma, represent 25% of all breast cancers. The histological diversity of breast carcinomas has relevant prognostic implications. Indeed, the rare breast cancer group includes subtypes with very different prognoses, ranging from the tubular carcinoma, associated with an indolent clinical course, to metaplastic cancer, whose outcome is generally unfavorable. New approaches based on gene expression profiling allow the identification of molecularly defined breast cancer classes, with distinct biological features and clinical behavior. In clinical practice, immunohistochemical classification based on the expression of human epidermal growth factor receptor 2 and Ki67 is applied as a surrogate of the intrinsic molecular subtypes. However, the identification of intrinsic molecular subtypes were almost completely limited to the study of ductal invasive breast cancer. Moreover, some good-prognosis triple-negative histotypes, on the basis of gene expression profiling, can be classified among the poor-prognosis group. Therefore, histopathological classification remains a crucial component of breast cancer diagnosis. Special histologies can be very rare, and the majority of information on outcome and treatments derives from small series and case reports. As a consequence, clear recommendations about clinical management are still lacking. In this review, we summarize current knowledge about rare breast cancer histologies.Breast cancer encompasses a collection of different diseases characterized by different biological and pathological features, clinical presentation, response to treatments, clinical behavior, and outcome. On the basis of cell morphology, growth, and architecture patterns, breast cancer can be classified in up to 21 distinct histological types. Breast cancer special types, including the classic lobular invasive carcinoma, represent 25% of all breast cancers. The histological diversity of breast carcinomas has relevant prognostic implications. Indeed, the rare breast cancer group includes subtypes with very different prognoses, ranging from the tubular carcinoma, associated with an indolent clinical course, to metaplastic cancer, whose outcome is generally unfavorable. New approaches based on gene expression profiling allow the identification of molecularly defined breast cancer classes, with distinct biological features and clinical behavior. In clinical practice, immunohistochemical classification based on the expression of human epidermal growth factor receptor 2 and Ki67 is applied as a surrogate of the intrinsic molecular subtypes. However, the identification of intrinsic molecular subtypes were almost completely limited to the study of ductal invasive breast cancer. Moreover, some good-prognosis triple-negative histotypes, on the basis of gene expression profiling, can be classified among the poor-prognosis group. Therefore, histopathological classification remains a crucial component of breast cancer diagnosis. Special histologies can be very rare, and the majority of information on outcome and treatments derives from small series and case reports. As a consequence, clear recommendations about clinical management are still lacking. In this review, we summarize current knowledge about rare breast cancer histologies. \ua9 AlphaMed Press

HER2DX genomic test in HER2-positive/hormone receptor-positive breast cancer treated with neoadjuvant trastuzumab and pertuzumab: A correlative analysis from the PerELISA trial

Biomarker; Breast cancer; Gene expressionBiomarcador; Càncer de mama; Expressió gènicaBiomarcador; Cáncer de mama; Expresión génicaBackground HER2DX is a prognostic and predictive assay in early-stage HER2-positive breast cancer based on clinical features and the expression of 4 gene signatures (immune, proliferation, luminal differentiation and HER2 amplicon), including ERBB2 mRNA levels. Here, we evaluated the ability of HER2DX to predict efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HER2-positive/hormone receptor-positive breast cancer. Methods HER2DX was evaluated on pre-treatment tumour samples from the PerELISA phase II study focused on postmenopausal patients with operable HER2-positive/hormone receptor-positive breast cancer. Patients received 2-weeks of letrozole, and then underwent a re-biopsy for Ki67 evaluation. Patients with endocrine therapy sensitive disease (ESD) (i.e., >20.0% Ki67 relative reduction at week 2) continued letrozole and 5 cycles of trastuzumab and pertuzumab. Primary aim was to test the ability of HER2DX risk-score, HER2DX pCR score and HER2DX ERBB2 mRNA score (as continuous variables and group categories) to predict pathological complete response (pCR) in patients with ESD. Logistic regression and receiver–operator curve (ROC) analysis assessed associations of HER2DX scores with pCR and ESD. Findings HER2DX was evaluated in 55 patients (86.0%) enrolled in PerELISA and 40 patients (73.0%) had ESD. The pCR rate in patients with ESD was 22.5% (9/40). In this group, HER2DX pCR score and HER2DX ERBB2 mRNA score were significantly associated with pCR (p = 0.008 and p = 0.003, univariate logistic regression model; area under ROC [AUC] = 0.803 and 0.896). The pCR rate in low, medium, and high HER2DX pCR score groups was 7.7% (2/26), 46.2% (6/13) and 100.0% (1/1), respectively. The pCR rate in low, medium, and high HER2DX ERBB2 score groups was 0.0% (0/12), 7.7% (1/13) and 53.3% (8/15), respectively. HER2DX pCR score was also significantly associated with Ki-67 response following 2-weeks of letrozole (p = 0.002, univariate logistic regression model; AUC = 0.775). The rate of ESD in low, medium, and high HER2DX pCR score groups was 89.7% (26/29), 65.0% (13/20) and 16.7% (1/6), respectively. Interpretation HER2DX predicts response following neoadjuvant letrozole in combination with dual HER2 blockade with trastuzumab and pertuzumab in early-stage HER2-positive/hormone receptor-positive breast cancer.This study received funding from Reveal Genomics

Gender influence on professional satisfaction and gender issue perception among young oncologists. A survey of the Young Oncologists Working Group of the Italian Association of Medical Oncology (AIOM)

Background: The professional gender gap is increasingly recognised in oncology. We explored gender issues perception and gender influence on professional satisfaction/gratification among young Italian oncologists. Methods: Italian oncologists aged 6440 years and members of the Italian Association of Medical Oncology were invited to participate in an online survey addressing workload/burnout, satisfaction in professional abilities and relations, relevant factors for professional gratification, and gender barriers. \u3c72 test for general association or \u3c72 test for trend was used to analyse the data. Results: 201 young oncologists participated in the survey: 67% female, 71% aged 30-40 years, 41% still in training and 82% without children. Women and men were equally poorly satisfied by the relations with people occupying superior hierarchical positions. There was heterogeneity between women and men in current (p=0.011) and expected future (p=0.007) satisfaction in professional abilities: women were more satisfied by current empathy and relations with colleagues and were more confident in their future managerial and team leader skills. The most important elements for professional gratification indicated by all participants were, in general, work-life balance (36%) and intellectual stimulation/research (32%); specifically for women, work-life balance (48%) and intellectual stimulation/research (20%); and specifically for men, career (29%) and social prestige/recognition (26%). Heterogeneity within the same gender emerged. For example, the elements indicated by men as the most important were intellectual stimulation/research (39%) and work-life balance (21%) in general, versus social prestige/recognition (24%) and career (24%), respectively, specifically for men (p<0.0001). More women versus men perceived gender issue as an actual problem (60% vs 38%, p=0.03); men underestimated gender barriers to women's career (p=0.011). Conclusions: Satisfaction in professional abilities varied by gender. Work-life balance is important for both women and men. Stereotypes about gender issues may be present. Gender issue is an actual problem for young oncologists, mostly perceived by women

Solitary biceps muscle metastasis from neuroendocrine breast tumor.

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ERBB2 mRNA as predictor of response to anti-HER2 antibody-drug conjugates (ADC) in breast cancer (BC)

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Validation of the American Joint Committee on Cancer new prognostic stage groups for HER2-positive breast cancer patients treated with adjuvant chemotherapy and trastuzumab in the prospective ShortHER trial

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Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management

The assessment of hormone receptors (HRs) and human epidermal growth factor receptor (HER)-2 is necessary to select patients who are candidates for hormonal and anti-HER-2 therapy. The evaluation of these parameters is generally carried out in primary tumors and it is not clear if reassessment in metastatic lesions might have an impact on patient management. The primary aim of this analysis was to compare HER-2 and HR status in primary tumors versus metastatic sites in breast cancer patients. PATIENTS AND METHODS: Seventy-five patients with available samples from primary tumors and paired metastases were included. HER-2 status was evaluated by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH); HR status was assessed by IHC. RESULTS: Nineteen percent of primary tumors were HER-2 positive; 77% were HR positive. Sites of biopsied or resected metastases were: locoregional soft tissues (n = 30), liver (n = 20), central nervous system (n = 5), bone (n = 5), pleura (n = 4), distant soft tissues (n = 3), abdomen (stomach, colon, peritoneum) (n = 3), bronchus (n = 3), and bone marrow (n = 2). For paired metastases, the HER-2 status was unchanged in 84% of cases; two patients changed from positive to negative, while 10 patients converted from negative to positive (agreement, 84%; kappa = 0.5681). A change in HR status was observed in 16 cases (21%): nine cases from positive to negative and seven cases from negative to positive (agreement, 78.7%; kappa = 0.4158). CONCLUSIONS: Further studies are necessary to better define the level of discordance in HER-2 or HR status between primary tumors and paired metastases. However, a biopsy of metastatic disease can be recommended, if feasible with minimal invasiveness, because treatment options might change for a significant proportion of patient

Integration of tumour infiltrating lymphocytes, programmed cell-death ligand-1, CD8 and FOXP3 in prognostic models for triple-negative breast cancer: Analysis of 244 stage I-III patients treated with standard therapy.

Tumour infiltrating lymphocytes (TILs) are an established prognostic biomarker for triple-negative breast cancer (TNBC). We evaluated the role of programmed cell-death ligand-1 (PD-L1), CD8 and FOXP3 expression in refining a prognostic model for non-metastatic TNBC beyond classic factors and TILs.Primary tumour samples from 244 early patients with TNBC, all treated with surgery and chemotherapy, were collected. Stromal TILs were evaluated on haematoxylin-eosin slides according to guidelines. PD-L1, CD8 and FOXP3 were assessed by immunohistochemistry and evaluated by digital pathology.TILs, PD-L1, CD8 and FOXP3 were positively correlated with each other (P 0.001). TILs were confirmed as an independent prognostic factor. When PD-L1, CD8 and FOXP3 were added to multivariable models including classic factors (age, stage, histologic grade) and TILs, PD-L1 provided the largest amount of additional prognostic information: likelihood ratio χBeyond clinicopathological factors and TILs, other immune biomarkers may add prognostic information for early TNBC. The increased PD-L1 expression on residual disease after neoadjuvant chemotherapy strengthens the rationale of testing immune checkpoint inhibitors in the post-neoadjuvant setting