a bad tumor biomarker is as bad as a bad drug the gap between genomics data and phenotype to predict response

The search for novel prognostic and predictive parameters in breast carcinoma is relentless. The new technological advances in gene expression profiling and in mutational analysis will hopefully prove to be clinically useful in informing the choice for the systemic therapy. For the time being, we are still relying in established immunohistochemical markers, namely estrogen and progesterone receptors, HER2 and Ki67. Advances in the harmonization of pre-analytical, analytical and interpretative variables may improve accuracy and reproducibility of the results

characterization and clinical impact of residual disease after neoadjuvant chemotherapy

Abstract One of the most important lessons learned from trials of neoadjuvant chemotherapy (NACT) is that achievement of pathological complete response (pCR) is a powerful prognostic predictor of long-term outcome, with significantly better disease-free and overall survival for patients achieving pCR, as compared with patients having residual tumour after NACT. The pathologists' role in the neoadjuvant setting is: (i) to ensure an accurate assessment of pCR, and (ii) to evaluate burden and biological characteristics of residual tumour if pCR has not been achieved. A conversion of receptor status from the core biopsy to the post-NACT surgical specimen may cause uncertainty in the choice of the post-surgical systemic treatment for the patients. It is therefore imperative to ensure accuracy in the assessment of ER, PgR and HER2, and to double check any apparent conversion by re-staining the previous core biopsy and the residual tumour in the same run, thus minimizing the technical artifacts, and to use both immunohistochemical and in situ hybridization assays to evaluate HER2 status. It is essential that protocols for evaluation of tumour response and for assessment of prognostic/predictive parameters of residual disease after NACT be eventually harmonized

integrating molecular profiling histological type and other variables defining the fingerprint of responsiveness to treatment

Summary The landscape of prognostication and prediction of responsiveness to systemic therapy for breast cancer patients has been recently enriched by the development of molecular assays, which enable to explore the whole universe of gene expression in the tumour cells and to unveil new prognostic and predictive markers. These molecular markers might well be used in combination with the established ones to address the many open questions that still pave the way to a truly personalized treatment. The actual clinical utility of the molecular assays is being tested in randomized clinical trials that require an unprecedented coordination of the activity of clinical investigators, pathologists and translational researchers worldwide

Pathological work up of the primary tumor: Getting the proper information out of it

Summary The primary tumour of patients with early breast cancer is the main source of information to assess the risk of disease recurrence and to inform the choice of the most appropriate systemic treatment. Accordingly, it is the main responsibility of the pathologists to ensure the patients and treating physicians that all the relevant information is derived from the primary tumour with the highest accuracy and reproducibility. The morphological changes of the tumour cells reflect the aggregate effects of changes occurring in hundreds of genes and may be a very faithful mirror of the biological and clinical behaviour of breast cancer. According to the 2009 St. Gallen Consensus, the systemic therapy of early breast cancer is mainly informed by the expression of hormone receptors and by the HER2 status, and the assessment of Ki67 has been included among the useful parameters to inform the choice of adding chemotherapy to endocrine therapies for patients with ER-positive and HER2-negative disease. A comprehensive approach that includes the accurate evaluation of the morphological features of the tumour, with special reference to the histological type and grade, and the assessment of the main prognostic and predictive parameters (ER, PgR, HER2 and Ki67) should offer to the patients and the treating physicians a robust background upon which the final therapeutic decisions can be safely taken

role of pathology in the management of advanced breast cancer

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Salivary gland choristoma of breast.

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lessons on responsiveness to adjuvant systemic therapies learned from the neoadjuvant setting

Summary Aims Recommended principles for the choice of therapies in operable breast cancer include the recognition of diverse subtypes of breast cancer and, based on genetic signature and immunohistochemistry, the identification of targets and related factors predictive of response. We review recent developments in the knowledge of established predictive factors in the neo-adjuvant setting. Methods and Results Experimental and clinical studies have shown that the degree of expression of estrogen receptor (ER) and progesterone receptor (PgR) of the primary tumor defines distinct biological entities that require a differentiated approach to neoadjuvant treatment and clinical trial investigation. In particular, tumors that express high levels of both steroid hormone receptors in a majority of cells derive no or low benefit from preoperative chemotherapy, while the absence of expression of ER and PgR was significantly correlated with the probability of pathologic complete remission (pCR). It was also demonstrated that the pCR rate to primary chemotherapy is significantly lower in invasive lobular carcinoma, frequently characterized by a high expression of steroid hormone receptors, if compared with the ductal histotype. Direct or indirect measures of high cell proliferation (elevated Ki-67 labeling index and high grade) identified patients with tumors responsive to chemotherapy in the preoperative setting. These factors might therefore assist in the identification of patients who might benefit from chemotherapy, in particular those patients with endocrine responsiveness. HER2 overexpression or amplification represents a target for neoadjuvant treatment with the humanised monoclonal antibody against its extracellular domain, but is also a factor predictive of response to neoadjuvant systemic therapies. A statistically significant positive correlation between HER2 positivity and pCR rate in patients treated with neoadjuvant chemotherapy was recently shown. Conclusions Results from studies in the neoadjuvant setting indicate that the use of factors predictive of response may permit a more effective application of therapies identifying patients likely to obtain substantial benefit from treatment

Tumour infiltrating lymphocytes (TILs) in breast cancer during pregnancy

Tumour infiltrating lymphocytes (TILs) is one of the most exciting breast cancer biomarkers, yet no data is available on its prevalence in tumours diagnosed during pregnancy.We evaluated the prevalence of TILs (stromal and intratumoural) in pregnant and non-pregnant young breast cancer patients.11/116 (9.6%) of the non-pregnant and 2/86 (2.3%) pregnant patients had TILs ≥ 50% (p 0.001) with highest prevalence observed in triple negative tumours (p = 0.01).This is the first report on TILs in tumours diagnosed during pregnancy. The low prevalence could reflect the state of low host immunity associated with pregnancy

Management of triple negative breast cancer

Triple negative breast cancer (TNBC) accounts for approximately 15% of breast cancer cases. TNBC is an immunohistochemically defined subtype, with significant diversity within the subtype. Generally TNBC occurs in younger women and is marked by high rates of relapse, visceral and CNS metastases, and early death. Current therapy fails to curtail the innate aggressive behaviour of TNBC in the majority of patients. The poor prognosis coupled with a lack of targeted use of therapies is reflected in the high mortality. In a minority of patients with highly chemosensitive disease, no robust clinical evidence exists to guide use of current cytotoxics. Critical to optimal future management are accurate identification of truly triple negative disease and adequately powered prospective TNBC trials to establish treatment efficacy and define predictive biomarkers