TAILORED MANAGEMENT OF ADVANCED BREAST CANCER: IS IT WORTH TO TAKE A BIOPSY OF METASTATIC SITES?

Breast cancer is a clinically and molecularly heterogeneous disease. The molecular classification represents the foundation of treatment selection for early and advanced breast cancer: endocrine manipulation and/or HER2 targeted agents are administered on the basis of oestrogen and progesteron receptors and HER2 expression. In routine clinical practice, the assessment of these predictive parameters (ER, PR and HER2) is usually carried out in the primary tumor, and these results are also used to guide treatment choice in metastatic disease, even if it occurred many years after the primary diagnosis. However, the appropriateness of this approach can now be questioned for some reasons. First of all, several reports have been published showing a lack of concordance in the expression of HER2 and hormonal receptors between primary tumors and disease recurrence, with range of discordance between 0% and 34% and between 18% and 54% respectively. According to the literature data, we have observed in a retrospective study of 75 patients an overall disagreement of 16% in the HER2 status (ten patients changed from negative to positive, two cases only from positive to negative) and of 21% in the expression of hormonal receptors (nine cases changed from positive to negative and seven cases from negative to positive) from primary tumors to disease recurrences. Noteworthy, it has recently been reported that also PI3KCA mutation occurs with high frequency but differently in primary and metastatic breast cancer (PIK3CA mutation was detected in 45% of the primary tumors and in 53% of paired metastases). The increasing use in the adjuvant setting of targeted agents might exert selective pressure, possibly facilitating a modification in tumor phenotype: in fact, the change from a positive to negative hormonal receptor or HER2 status might reflect acquired resistance to hormonal or anti-HER2 therapy. But the finding that receptor status can change to both directions not support the hypothesis that during tumor progression, de-differentiation always occurs leading to a more aggressive phenotype. At the same time the conversion from a negative to positive phenotype can offer the patient the opportunity to receive a treatment that possibly could ameliorate the outcome: this issue has obviously direct relevance for treatment decision-making. Furthermore, new imaging and radiological techniques (e.g., ultrasound or computed tomography–guided biopsy) have improved our ability to easily and safely obtain tissue samples from metastatic sites. The mechanisms underlying the change in the expression of hormonal receptors and HER2 have yet to be completely understood. According to intratumoral heterogeneity theory a clone with metastatic potential could not be detected in the primary lesion and could form metastatic deposits with different biologic properties. Another way is a possible genetic drift or a clonal selection which occurs during tumor progression or a selective pressure of prior therapies (as mentioned above). Finally the technical reproducibility of the ER, PR and HER2 assay could in part justify the rates of discordance, because immunohistochemistry or FISH have less than 100% of accuracy and reproducibility. Several studies indicate that even when consecutive slides from the same tumor block are stained in different laboratories or interpreted by different pathologists, significant levels of discordance rates are found; differences in fixation methods, choice of antibody and threshold levels can also have a profound effect on immunohistochemistry results. In summary, a substantial rate of discordance in pathology and molecular markers between primary breast cancer and asynchronous metastases is possible and can alter the patient management in up to 20% of them. Tissue confirmation should be considered standard of care in patients with clinical and/or radiological suspicion of metastatic recurrence and lesions amenable to biopsy with minimal invasiveness

TREATMENT OF EARLY HER2+ BREAST CANCER: ACHIEVEMENTS AND UNMET NEEDS

Among breast cancers diagnosed at any stage, 20%–30% are found to have HER2 gene amplification/receptor overexpression that is associated with aggressive behaviour (high proliferative activity, metastatic potential and neoangiogenesis) and poor outcome. Trastuzumab, the humanized monoclonal antibody against HER2 receptor, is an essential component of the treatment of patients with HER2-positive breast cancer that has change the biological history of the disease. In the adjuvant setting, the results of six phase III randomized trials with more than 10,000 HER2-positive breast cancer patients have been presented so far; different chemotherapy regimens and different modalities of trastuzumab administration (in combination or sequentially after chemotherapy) have been explored. Five trials have demonstrated the superiority of adding trastuzumab to chemotherapy compared with chemotherapy alone (the DFS was 33%–52% greater independently from age, nodal status, hormonal status, or tumor size and the OS was 34%–41% greater), while only PACS04 trial has shown no benefit for adding trastuzumab at the completion of chemotherapy versus control. The majority of these trials have tested one year of trastuzumab therapy. But the HERA trial is the only one specifically designed to test prospectively different durations of trastuzumab administered with sequential approach (that is at the end of adjuvant chemotherapy), with positive results in terms of DFS and OS; up to now, the results of the comparison of 1 versus 2 years of treatment are still not yet available. Moreover, the cytotoxic synergism of combined trastuzumab and chemotherapy is supported not only by the previous mentioned trials, but also by clinical data in metastatic (25% survival increase) and neoadjuvant settings (26.3% of pCR without and 66.7% of pCR with trastuzumab respectively in the MDACC experience). Interestingly, a small Finnish study wherein trastuzumab was administered for a very short period (9 weekly administrations) concomitantly with chemotherapy suggested that a shorter treatment might produce comparable efficacy with significant lower toxicities. The cardiac safety of trastuzumab is in fact another relevant clinical issue, particularly when it is used as adjuvant therapy. In all the adjuvant trastuzumab trials, despite the selection of the optimal patient population, symptomatic congestive heart failure occurred in 1.5%-2.5% of the patients treated with sequential trastuzumab (HERA trial, PACS 04, and N9831 arm B) and in a percentage ranging from 0.4 (BCIRG006 arm C, without anthracyclines) to 3.6 of the patients in the trials in which trastuzumab was started concomitantly with chemotherapy (BCIRG 006 arm B, N9831 arm C, NSABP B-31); moreover, a significant proportion of patients never started trastuzumab because of LVEF decline (1.9-6.4%) or did not complete the planned trastuzumab therapy due to cardiac events (6-18%). To test the hypothesis that a shorter duration of adjuvant trastuzumab concomitant with chemotherapy might be effective but less toxic, we have designed a phase III multicentre, randomized trial in order to evaluate if short (9 weekly administrations) versus long (18 three-weekly administrations) adjuvant trastuzumab combined with chemotherapy is equally effective in terms of DFS, and less toxic from a cardiac viewpoint. Other European trials are addressing the same questions (PHARE trial, SOLD trial, PERSEPHONE trial), but in addition this trial will explore less intensive adjuvant trastuzumab regimens in the node negative pT1a,b HER2 positive breast cancer population so poorly represented in most clinical trials. At the same time, Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) is a four-arm randomized trial designed to compare adjuvant trastuzumab and lapatinib in women with early-stage HER2-positive breast cancer: it examine which anti-HER2 agent is more effective and which is the best schedule of administration, namely, what benefit will be derived by taking the drugs separately, in tandem order or in combination. Moreover, the TEACH trial is designed to determine whether adjuvant therapy with lapatinib for 1 year will improve DFS. Finally, the strategy for using adjuvant trastuzumab monotherapy with or without endocrine therapy, for tumors judged to be low risk by routine clinico-pathological or molecular assessment is till controversial. In summary, many questions related to trastuzumab use in the adjuvant setting still remain unanswered, regarding to the optimum timing and duration of treatment, its role in small node-negative tumors, the optimum therapy regimens

Moralidade social e ideal individual

Tradução para o português do ensaio "Social Morality and Individual Ideal”. Publicado originalmente em Philosophy: The Journal of the Royal Institute of Philosophy, vol. XXXVI, n. 136, p. 1-17, Jan. 1961. Republicado em: STRAWSON, P. F. Freedom and Resentment and Other Essays. Londres: Methuen, 1974. [Routledge, 2008, p. 26-44]. ]. Publicado na coletânea: Ensaios sobre a filosofia de Strawson: com a tradução de Liberdade e ressentimento & Moralidade social e ideal individual. Organizadores: Jaimir Conte & Itamar Luís Gelain. Editora da UFSC, 2015. ISBN: 978853280725

Meromorphic traveling wave solutions of the complex cubic-quintic Ginzburg-Landau equation

We look for singlevalued solutions of the squared modulus M of the traveling wave reduction of the complex cubic-quintic Ginzburg-Landau equation. Using Clunie's lemma, we first prove that any meromorphic solution M is necessarily elliptic or degenerate elliptic. We then give the two canonical decompositions of the new elliptic solution recently obtained by the subequation method.Comment: 14 pages, no figure, to appear, Acta Applicandae Mathematica

Semiclassical Vibrational Spectroscopy of Biological Molecules Using Force Fields

Semiclassical spectroscopy is a practical way to get an accurately approximate quantum description of spectral features starting from ab initio molecular dynamics simulations. The computational bottleneck for the method is represented by the cost of ab initio potential, gradient, and Hessian matrix estimates. This drawback is particularly severe for biological systems due to their unique complexity and large dimensionality. The main goal of this manuscript is to demonstrate that quantum dynamics and spectroscopy, at the level of semiclassical approximation, are doable even for sizable biological systems. To this end, we investigate the possibility of performing semiclassical spectroscopy simulations when ab initio calculations are replaced by computationally cheaper force field evaluations. Both polarizable (AMOEBABIO18) and nonpolarizable (AMBER14SB) force fields are tested. Calculations of some particular vibrational frequencies of four nucleosides, i.e., uridine, thymidine, deoxyguanosine, and adenosine, show that ab initio simulations are accurate and widely applicable. Conversely, simulations based on AMBER14SB are limited to harmonic approximations, but those relying on AMOEBABIO18 yield acceptable semiclassical values if the investigated conformation has been included in the force field parametrization. The main conclusion is that AMOEBABIO18 may provide a viable route to assist semiclassical spectroscopy in the study of large biological molecules for which an ab initio approach is not computationally affordable