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

MANAGEMENT OF ADVANCED BREAST CANCER: HOW TO INTEGRATE SCIENTIFIC DATA AND CLINICAL JUDGMENT

Recent epidemiological data have shown a significant decline in breast cancer mortality over the past 15 years, as a result of screening programs, better education, and the introduction of more effective adjuvant treatments1. However, about 20-30% of the patients eventually relapse while approximately 5-7% of cases present with metastatic disease at diagnosis2. Metastatic breast cancer is still largely incurable: the median survival time is generally in the range of 2 to 4 years3. In the metastatic setting, treatment goals can be quite different depending on patient and tumor characteristics. There are patients for whom the main objective is symptom control to improve or maintain quality of life, cases with life-threatening disease for whom a rapid tumor shrinkage is required, asymptomatic patients with slowly growing disease for whom a prolonged progression-free survival (PFS) duration is the desirable target; finally, some patients can obtain an important survival prolongation and a few of them might be cured4. The selection of treatment depends on several factors, including patient characteristics, aggressiveness of the disease, response to previous therapies, time since last exposure, agents used in the past and cumulative doses. Availability and regulatory approval of various anticancer agents further diversify treatment patterns in different part of the world. A rapidly growing pool of effective treatment options for advanced breast cancer has increased response rates and outcome. First, many new cytotoxic drugs are in development or have recently been approved in this setting, such as ixabepilone, eribulin and nab-paclitaxel. For instance, in the phase III trial EMBRACE, eribulin mesylate improved overall survival (median 13.1 months, 95% CI 11.8-14.3), compared to treatment of physician’s choice (median 10.6 months, CI 9.3-12.5; HR 0.81 95% CI 0.66-0.99, p=0.041), in patient who had received two to five prior chemotherapy regimens, including an anthracycline and a taxane for advanced breast cancer.5 In clinical studies, 3-weekly nab-paclitaxel has been shown to increase both the safety and the efficacy of 3-weekly paclitaxel in patients with advanced breast cancer (median time to progression 23 vs 16.9 weeks, hazard ratio 0.75, p=0.006).6 Weekly nab-paclitaxel produced meaningful results even in taxanes pre-treated patients (ORR 14% and 16% in the 100 and 125 mg/sqm cohorts, respectively; median PFS of 3 and 3.5 months, respectively).7 At the same time, research efforts are directed to implement the pool of targeted therapies, in order to offer more individualized options to breast cancer patients. In fact, the molecular breast cancer subtype is a fundamental determinant of treatment choice both in early and advanced setting. Breast cancer consists of at least three different diseases: hormone-sensitive breast cancer, the human epidermal growth factor receptor (HER2)-positive subtype, and triple-negative disease. Each molecular subtype has distinct biological features and a distinct clinical course: hormone receptor–positive (HR+) disease is generally characterized by a more indolent course, with a long disease-free interval (DFI) and a tendency to relapse in the bone or soft tissues; amplification of the HER-2 gene confers a more aggressive clinical behavior to the HR+ subgroup, with a higher propensity for visceral relapses. Both triple-negative breast cancer and hormone receptor–negative (HR-)/HER-2+ breast cancer are aggressive subtypes, with early visceral or central nervous system metastases. Each molecular subtype requires distinct therapeutic approaches. In HR+ tumors, endocrine manipulation is the cornerstone of therapy. Treatment choice depends on many factors such as menopausal status and disease-free interval. For postmenopausal women many agents are available: non-steroidal and steroidal aromatase inhibitors (AI), tamoxifen and fulvestrant; however no definitive recommendation for the optimal cascade can be given. For premenopausal patients, the data on aromatase inhibitors or fulvestrant are more scanty8. In case of life-threatening and rapidly-growing disease, or in case of failure of various endocrine agents, chemotherapy has to be considered. Yet, recent studies have shown that HR+ positive tumors do also derive benefit from additional targeted agents: data from the BOLERO-2 trial showed an impressive improvement in progression free-survival with the addition of everolimus to exemestane vs exemestane alone as first- or second-line treatment for HR+ advanced breast cancer patients, after failure of a non-steroidal AI in the adjuvant or metastatic setting (median PFS 10.6 vs 4.1 months according to central assessment, HR 0.36;95% CI 0.27-0.47, p<0.001)9. Thus, overcoming endocrine resistance by combined targeting of redundancy pathways will be one of the key issues in the near future. In this context, even the association of trastuzumab or lapatinib to endocrine agents is an important option for HR+/HER2+ patients. Targeting HER2 in HR+ breast cancer has been explored as a means of improving endocrine responsiveness. The randomized phase II TAnDEM trial included 207 patients with known ER+/HER2+ metastatic breast cancer and reported a doubling of progression-free survival with the addition of trastuzumab over anastrozole alone (hazard ratio 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4 months; p =0016)10. Finally, results from a phase III trial of 1,286 patients with metastatic ER+ breast cancer who were randomized to receive either letrozole alone or letrozole combined with lapatinib have been published. In patients with known ER+/HER2+ tumors (n=219), the addition of lapatinib to letrozole significantly reduced the risk of progression as compared to letrozole alone: median PFS was 8.2 v 3.0 months, respectively (HR 0.71; 95% CI, 0.53 to 0.96; p=0.019)11. In HR-/HER2+ tumors, the incorporation of trastuzumab has substantially reversed the negative prognostic impact of HER-2 overexpression/amplification12. However, due to the approval of trastuzumab as standard adjuvant therapy for early HER2+ breast cancer and the emergency of resistance to this drug, the need of new anti-HER2 agents has emerged, as well as the need to clarify the role of continuing trastuzumab beyond progression, with different cytotoxic agents. Lapatinib, combined with capecitabine, has been approved for the treatment of HER2+ metastatic breast cancer patients, previously treated with trastuzumab. Many other anti-HER2 agents are being developed such as T-DM1, neratinib and pertuzumab. In T-DM1 trastuzumab is conjugated with an antimicrotubule drug maytansinoid. Activation of cytotoxicity of this conjugate requires internalization into the cell after binding to HER2. A single-arm, phase II trial (n = 112 MBC patients whose disease progressed on trastuzumab) showed at a follow-up of ≥12 months a median PFS of 4.6 months (95% CI, 3.9 to 8.6) and an overall response rate of 26%. Hypokalemia, thrombocytopenia, and fatigue were the most common observed adverse events. No dose-limiting cardiotoxicity was reported13. T-DM1 is undergoing further testing in the context of several other studies. An open-label, phase III randomized trial (EMILIA) is comparing single-agent T-DM1 with the combination of capecitabine and lapatinib in patients whose HER2-positive disease has progressed on trastuzumab. In another phase III trial MARIANNE, T-DM1 monotherapy is being compared to trastuzumab plus a taxane. Neratinib/HKI-272 is an oral, irreversible, small molecule inhibitor of EGFR/HER1, HER2, and HER4. In an open-label, phase II study, patients with advanced HER2-positive BC with and without prior trastuzumab treatment received neratinib. The 16-week PFS was 59% for patients with prior trastuzumab (n = 63) and 78% for those without (n = 64); median PFS were 22.3 and 39.6 weeks, respectively. The most frequent AEs were diarrhea, nausea, vomiting, and fatigue. Grade 3 or 4 diarrhea occurred in 30% of patients with prior trastuzumab therapy, leading to neratinib dose reduction in 29% of this cohort14. A phase III randomized study of paclitaxel with either neratinib or trastuzumab in MBC is ongoing, as is a randomized phase II study of neratinib alone versus the combination of capecitabine and lapatinib. Pertuzumab is a first-in-class recombinant, humanized monoclonal antibody that binds to domain II of the HER2 receptor, thus inhibiting HER2 heterodimerization with HER1, HER3, and HER4. Recent data from a randomized phase III trial showed that the combination of trastuzumab, pertuzumab and docetaxel as first-line treatment for HER2+ advanced breast cancer patients, significantly improves progression-free survival, with a gain of 6 months in median progression-free survival, as compared to the combination of trastuzumab and docetaxel (PFS 18.5 vs 12.4 months, HR 0.62; 95% CI, 0.51 to 0.75; P<0.001)15. These results contribute to increase the interest in dual HER2 blockade that derived from early breast cancer trials. In this context, the combination of trastuzumab and lapatinib in trastuzumab-pretreated patients resulted in a more prolonged PFS as compared to lapatinib alone (HR 0.73; 95%CI 0.57-0.93, p=0.008)16. Lastly, chemotherapy is the only available option so far for the triple-negative (TNBC) subtype, which is characterized by the absence of hormone receptors and HER-2 negativity. At this time, there are no targeted agents that are specifically approved for the treatment of this breast cancer subtype. Bevacizumab appears to prolong progression-free survival when added to chemotherapy for patients with TNBC (as it does for those with HR+/HER2- disease), but does not enhance survival17. Moreover, neoadjuvant trials provide conflicting results on the role of bevacizumab for TNBC18,19. Although there was great enthusiasm based on phase II data for the combination of carboplatin, gemcitabine and the PARP-inhibitor iniparib, the phase III results did not support the preliminary data20. A variety of other targeted therapies, including the PI3K inhibitors and a number of agents that inhibit DNA repair are under active investigation. Nowadays, more patients are likely to be diagnosed with oligo-metastatic disease, asymptomatic and in good performance status, due to the use of more sophisticated imaging techniques and the information derived from serum-markers dosage; therefore more selective therapeutic strategies that include a multimodality approach and local therapies are becoming more and more important. A substantial improvement in multimodality treatments, including, but not limited to, stereotactic radiosurgery, percutaneous radiofrequency ablation, and minimally invasive surgery, has increased the chance for disease control in selected patients with limited and indolent metastatic disease. In this context, surgery on primary tumor in case of oligometastatic disease has been suggested to improve survival, but further data are needed and a randomized trial addressing this issue is ongoing. Furthermore, an interesting field of research is the molecular characterization of metastatic disease. Biopsies of recurrent sites are not routinely performed and treatment decision for metastatic disease is mainly based on the receptor status of the primary tumor. However, discordance rates in HR and/or HER2 status between primary and recurrent tumors have been reported in the range of 10% to 35%21. Reasons for discordance may include: test artifacts, tumor heterogeneity, genetic drift during progression, selective pressure of adjuvant therapies. Nevertheless, recent reports suggest that the change in the receptor status during tumor progression may have also a prognostic impact22. It is therefore critical to incorporate all disease and patient information to assure the best treatment strategy for a given patient. The choice of the best treatment for metastatic disease has become even more difficult because the more efficacious agents have been progressively incorporated into the management of earlier stages. As a consequence, even if the number of patients who experience disease recurrence is gradually decreasing, treatment options for recurring patients are more and more influenced by prior exposure to adjuvant therapy. Unfortunately, most trials conducted in advanced breast cancer do not take into account all these factors that are necessary for an appropriate decision-making process. A deeper insight into tumor biology and mechanisms of resistance to established therapies will allow to develop new cytotoxic or targeted drugs or new combinations of available drugs for the treatment of metastatic disease. Key preclinical studies are needed, in order to guide the choice of which combination or single-agent deserve to be tested in early phase clinical trials. Moreover, well-designed trials that take into account the critical issues that frequently present in clinical routine are needed, in order to allow for a better translation of scientific results into daily practice

A stoichiometric solvent-free protocol for acetylation reactions

Considering the remarkable relevance of acetylated derivatives of phenols, alcohols, and aryl and alkyl thiols in different areas of biology, as well as in synthetic organic chemistry, a sustainable solvent-free approach to perform acetylation reactions is proposed here. Acetylation reactions are classically performed using excess of acetic anhydride (Ac2O) in solvent-free conditions or by eventually working with stoichiometric amounts of Ac2O in organic solvents; both methods require the addition of basic or acid catalysts to promote the esterification. Therefore, they usually lead to the generation of high amounts of wastes, which sensibly raise the E-factor of the process. With the aim to develop a more sustainable system, a solvent-free, stoichiometric acetylation protocol is, thus, proposed. The naturally occurring phenol, thymol, can be converted to the corresponding-biologically active-ester with good yields, in the presence of 1% of VOSO4. Interestingly, the process can be efficiently adopted to synthesize other thymyl esters, as well as to perform acetylation of alcohols and aryl and alkyl thiols. Remarkably, a further improvement has been achieved replacing Ac2O with its greener alternative, isopropenyl acetate (IPA)

Tailored functionalization of natural phenols to improve biological activity

Phenols are widespread in nature, being the major components of several plants and essential oils. Natural phenols' anti-microbial, anti-bacterial, anti-oxidant, pharmacological and nutritional properties are, nowadays, well established. Hence, given their peculiar biological role, numerous studies are currently ongoing to overcome their limitations, as well as to enhance their activity. In this review, the functionalization of selected natural phenols is critically examined, mainly highlighting their improved bioactivity after the proper chemical transformations. In particular, functionalization of the most abundant naturally occurring monophenols, diphenols, lipidic phenols, phenolic acids, polyphenols and curcumin derivatives is explored