mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) plays a crucial role in the control of cellular growth, proliferation, survival, metabolism, angiogenesis, transcription, and translation. In most human cancers, alterations to this pathway are common and cause activation of other downstream signaling pathways linked with oncogenesis. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both tumor immunity and angiogenesis. Inflammation is a hallmark of cancer, playing a central role in the tumor dynamics, and immune cells can exert antitumor functions or promote the growth of cancer cells. In this context, mTOR may regulate the activity of macrophages and T cells by regulating the expression of cytokines/chemokines, such as interleukin (IL)-10 and transforming growth factor (TGF-ß), and/or membrane receptors, such as cytotoxic T-Lymphocyte protein 4 (CTLA-4) and Programmed Death 1 (PD-1). Furthermore, inhibitors of mammalian target of rapamycin are demonstrated to actively modulate osteoclastogenesis, exert antiapoptotic and pro-differentiative activities in osteoclasts, and reduce the number of lytic bone metastases, increasing bone mass in tumor-bearing mice. With regard to the many actions in which mTOR is involved, the aim of this review is to describe its role in the immune system and bone metabolism in an attempt to identify the best strategy for therapeutic opportunities in the metastatic phase of solid tumors.

Takotsubo Syndrome during Pertuzumab and Trastuzumab Therapy for HER2-Positive Metastatic Breast Cancer.

Pertuzumab and trastuzumab have been shown to improve the outcomes of patients with metastatic breast cancer, with a rate of left ventricular dysfunction of approximately 6%. We report the case of a postmenopausal woman who presented with Takotsubo syndrome during maintenance therapy with pertuzumab and trastuzumab, in association with fulvestrant (an anti-estrogen) and denosumab. After normalization of cardiac function, therapy with pertuzumab and trastuzumab was resumed in the absence of new cardiac toxicity. We report the first clinical case of Takotsubo syndrome during double anti-HER2 blockade in association with an antiestrogen. Furthermore, we show how anti-HER2 therapy can be safely resumed after the detection of Takotsubo syndrome.

Role of Breast Cancer Risk Estimation Models to Identify Women Eligible for Genetic Testing and Risk-Reducing Surgery.

Hereditary breast and ovarian cancer (HBOC) syndrome is responsible for approximately 10% of breast cancers (BCs). The HBOC gene panel includes both high-risk genes, i.e., a four times higher risk of BC (BRCA1, BRCA2, PALB2, CDH1, PTEN, STK11 and TP53), and moderate-risk genes, i.e., a two to four times higher risk of BC (BARD1, CHEK2, RAD51C, RAD51D and ATM). Pathogenic germline variants (PGVs) in HBOC genes confer an absolute risk of BC that changes according to the gene considered. We illustrate and compare different BC risk estimation models, also describing their limitations. These models allow us to identify women eligible for genetic testing and possibly to offer surgical strategies for primary prevention, i.e., risk-reducing mastectomies and salpingo-oophorectomies.

Role of the Molecular Tumor Board for the Personalized Treatment of Patients with Metastatic Breast Cancer: A Focus on the State of the Art in Italy.

Molecular tumor boards (MTBs) are multidisciplinary groups that combine molecular and clinical data from cancer patients in order to formulate treatment recommendations for precision medicine. To date, there is insufficient data to support the use of singleplex or next-generation sequencing (NGS) technologies to select first-line therapy for patients with metastatic breast cancer (MBC), but considering the high number of level II alterations, according to the ESMO scale for clinical actionability of molecular targets (ESCAT), it is suggested to include patients in molecular screening programs in order to be able to offer targeted therapies for specific genomic alterations. This article aims at reviewing the most recent literature related to the most used methodologies/approaches for molecular diagnostics and variants' classification, summarizing the internationally published molecular screening studies in support of MTB activity and, in the end, discussing MTBs' current position and role in Italy, the number of which is increasing, also thanks to the thrust of institutions.

The VES-13 and G-8 tools as predictors of toxicity associated with aromatase inhibitors in the adjuvant treatment of breast cancer in elderly patients: A single-center study.

Background: Adjuvant hormone treatment of postmenopausal breast cancer is mainly based on aromatase inhibitors. Adverse events associated with such class of drugs are particularly severe in elderly patients. Therefore, we investigated the possibility of ab initio predict which elderly patients could encounter toxicity. Methods: In light of national and international oncological guidelines recommending the use of screening tests for multidimensional geriatric assessment in elderly patients aged ≥70 years and eligible for active cancer treatment, we assessed whether the Vulnerable Elder Survey (VES)-13 and the Geriatric (G)-8 could be predictors of toxicity associated with aromatase inhibitors. Seventy-seven consecutive patients aged ≥70 diagnosed with non-metastatic hormone-responsive breast cancer and therefore eligible for adjuvant hormone therapy with aromatase inhibitors, were screened with the VES-13 and the G-8, and underwent a six-monthly clinical and instrumental follow-up in our medical oncology unit, from September 2016 to March 2019 (30 months). Said patients were identified as vulnerable (VES-13 score ≥3 or G-8 score ≤14) and fit (VES-13 score <3 or G-8 score >14). The likelihood of experiencing toxicity is greater among vulnerable patients. Results: The correlation between the VES-13 or the G-8 tools and the presence of adverse events is equal to 85.7% (p = 0.03). The VES-13 demonstrated 76.9% sensitivity, 90.2% specificity, 80.0% positive predictive value, 88.5% negative predictive value. The G-8 demonstrated 79.2% sensitivity, 88.7% specificity, 76% positive predictive value, 90.4% negative predictive value. Conclusion: The VES-13 and the G-8 tools could be valuable predictors of the onset of toxicity associated with aromatase inhibitors in the adjuvant treatment of breast cancer in elderly patients aged ≥70.

Allostatic Load as an Insight into the Psychological Burden after Primary Treatment in Women with Breast Cancer: Influence of Physical Side Effects and Pain Perception.

Breast cancer (BC) diagnosis and treatment have become a cumulative long-standing chronic disease impairment, causing stress and turning into an allostatic load (AL) framework. This study aimed to investigate the relationship between physical issues and mental health in patients with BC after medical treatment. We conducted an observational study of 61 female patients with BC, and clinical and psychological markers have been detected. We conducted descriptive statistics, ANOVA analyses, correlations, and mediation analyses to verify the effect of the comorbidity index on psychological dimensions. The findings showed high levels of distress and moderate pain, and 32.8% of the patients showed moderate physical impairment. Significant effects of "age" and "physical issues" were found. The adult group reported a higher incidence of physical issues, and the group of patients reporting moderate physical impairment seemed more depressed than patients with mild physical issues. Finally, the comorbidity condition mediated the presence of signs of depression. Patients with BC seemed to experience negative emotions related to comorbidities associated with compromised activities of daily living. Our findings highlighted allostatic overload as a predictive framework to better understand the mental health of women with BC diagnoses to tailor effective psychological treatments for enhanced recovery.

Anthracycline-Free Neoadjuvant Treatment in Patients with HER2-Positive Breast Cancer: Real-Life Use of Pertuzumab, Trastuzumab and Taxanes Association with an Exploratory Analysis of PIK3CA Mutational Status.

HER2 is considered one of the most traditional prognostic and predictive biomarkers in breast cancer. Literature data confirmed that the addition of pertuzumab to a standard neoadjuvant chemotherapy backbone (either with or without anthracyclines), in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), leads to a higher pathological complete response (pCR) rate, which is known to correlate with a better prognosis. In this retrospective analysis, 47 consecutive patients with HER2-positive EBC received sequential anthracyclines and taxanes plus trastuzumab (ATH) or pertuzumab, trastuzumab and docetaxel (THP). Despite the limited sample size, this monocentric experience highlights the efficacy (in terms of pCR) and safety of THP in the neoadjuvant setting of HER2-positive EBC as an anthracycline-free approach. Given the role of PIK3CA as a prognostic and therapeutic target in breast cancer, tumors were also analyzed to assess the PIK3CA mutational status. Thirty-eight out of forty-seven patients were evaluated, and PIK3CA variants were identified in 21% of tumor samples: overall, one mutation was detected in exon 4 (2.6%), two in exon 9 (5.3%) and four in exon 20 (10.5%). Of note, one sample showed concurrent mutations in exons 9 (codon 545) and 20 (codon 1047). Among patients reaching pCR (n = 13), 38.5% were PIK3CA mutants; on the other hand, among those lacking pCR (n = 25), just 12% showed PIK3CA variants. Regarding THP-treated mutant patients (n = 5), 80% reached pCR (three hormone-receptor-negative, one hormone-receptor-positive). Interestingly, the only patient not achieving pCR had a tumor with two co-occurring PIK3CA mutations. In conclusion, this study provides new evidence about the efficacy and good safety profile of THP, compared to the ATH regimen, as an anthracycline-free neoadjuvant treatment of HER2-positive EBC. Further studies on larger/multicentric cohorts are planned for more in-depth analysis to confirm our molecular and clinical results.

NSCLC Immunotherapy and Related Rare Toxicities: A Monocentric Real-Life Experience.

BACKGROUND: In the last years immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC) not supported by a driver mutation. Immunotherapy related adverse events (irAEs) have a unique toxicity profiles distinct from the toxicities of classical chemotherapy treatment relating to their mechanism of action. We analyzed some serious and uncommon life-threatening irAEs, needing a change in the therapeutic strategy. METHOD: Between October 2018 and October 2020, 63 NSCLC patients underwent immunotherapy. Thirty-eight patients underwent first-line Pembrolizumab, 200 mg every 21 days (Group A). Twenty patients were treated in second line with Pembrolizumab 200 mg every 21 days or Nivolumab 240 mg every 14 days or Atezolizumab 800 mg every 14 days (Group B). Five stage III patients treated after radio chemotherapy with Durvalumab 1500 mg every 14 days (Group C). RESULTS: We experienced: a) 2 bowel perforations (3.2%), necessitating Hartmann's resection. Only one of the two patients restored immunotherapy; b) 1 chronic renal insufficiency (1.6%, creatinine up to 8 mg/dL) and 2 severe hypertransaminasemias (3.2%, up to 65 U/L), requiring the immediate and definitive interruption of ICIs; c) 2 pericardial effusions (3.2%), of which one needed subxiphoid pericardiocentesis for cardiac tamponade. Patient restored immunotherapy after resolution of the acute event. CONCLUSIONS: Immunotherapy include monoclonal antibodies reducing the suppression of effector T cells and improving the tumor-specific immune responses. Most common irAEs are evident in mild and reversible form, but sometimes life-threatening irEAs show up. Therefore, further clinical trials needed to increase knowledge of drugs and prevent unexpected irAEs.

The VES-13 and G-8 tools as predictors of toxicity associated with aromatase inhibitors in the adjuvant treatment of breast cancer in elderly patients: A single-center study.

Background: Adjuvant hormone treatment of postmenopausal breast cancer is mainly based on aromatase inhibitors. Adverse events associated with such class of drugs are particularly severe in elderly patients. Therefore, we investigated the possibility of ab initio predict which elderly patients could encounter toxicity. Methods: In light of national and international oncological guidelines recommending the use of screening tests for multidimensional geriatric assessment in elderly patients aged ≥70 years and eligible for active cancer treatment, we assessed whether the Vulnerable Elder Survey (VES)-13 and the Geriatric (G)-8 could be predictors of toxicity associated with aromatase inhibitors. Seventy-seven consecutive patients aged ≥70 diagnosed with non-metastatic hormone-responsive breast cancer and therefore eligible for adjuvant hormone therapy with aromatase inhibitors, were screened with the VES-13 and the G-8, and underwent a six-monthly clinical and instrumental follow-up in our medical oncology unit, from September 2016 to March 2019 (30 months). Said patients were identified as vulnerable (VES-13 score ≥3 or G-8 score ≤14) and fit (VES-13 score <3 or G-8 score >14). The likelihood of experiencing toxicity is greater among vulnerable patients. Results: The correlation between the VES-13 or the G-8 tools and the presence of adverse events is equal to 85.7% (p = 0.03). The VES-13 demonstrated 76.9% sensitivity, 90.2% specificity, 80.0% positive predictive value, 88.5% negative predictive value. The G-8 demonstrated 79.2% sensitivity, 88.7% specificity, 76% positive predictive value, 90.4% negative predictive value. Conclusion: The VES-13 and the G-8 tools could be valuable predictors of the onset of toxicity associated with aromatase inhibitors in the adjuvant treatment of breast cancer in elderly patients aged ≥70.

Invasive Ductal Breast Cancer with Osteoclast-Like Giant Cells: A Case Report Based on the Gene Expression Profile for Changes in Management.

We report the case of a 49-year-old woman diagnosed with a rare histotype of early breast cancer (BC), invasive ductal carcinoma with osteoclast-like giant cells (OGCs), from the perspective of gene profile analysis tests. The patient underwent a quadrantectomy of the right breast with removal of 2 cm neoplastic nodule and three ipsilateral sentinel lymph nodes. The Oncotype Dx gave a recurrence score (RS) of 23, and taking into account the patient's age, an RS of 23 corresponds to a chemotherapy benefit of 6.5%. After a multidisciplinary collegial discussion, and in consideration of the patient's age, the absence of comorbidity, the premenopausal state, the rare histotype and the Oncotype Dx report, the patient was offered adjuvant chemotherapy treatment followed by hormone therapy. This case may be an example of the utility of integrating gene expression profiling tests into clinical practice in the adjuvant treatment decision of a rare histotype BC. The Oncotype Dx test required to supplement the histological examination made us opt for the proposal of a combined treatment of adjuvant chemotherapy followed by adjuvant hormone therapy. It demonstrates the importance of considering molecular tests and, in particular, the Oncotype Dx, in estimating the risk of disease recovery at 10 years in order to identify patients who benefit from hormone therapy alone versus those who benefit from the addition of chemotherapy, all with a view toward patient-centered oncology. Here, we discuss the possible validity and limitations of the Oncotype Dx in a rare luminal A-like histotype with high infiltrate of stromal/inflammatory cells.

Sex and Gender Influences on Cancer Immunotherapy Response.

The global burden of cancer is growing and a wide disparity in the incidence, malignancy and mortality of different types of cancer between each sex has been demonstrated. The sex specificity of cancer appears to be a relevant issue in the management of the disease, and studies investigating the role of sex and gender are becoming extremely urgent. Sex hormones are presumably the leading actors of sex differences in cancer, especially estrogens. They modulate gene expression, alter molecules and generate disparities in effectiveness and side effects of anticancer therapies. Recently immunotherapy aims to improve anticancer treatment strategies reducing off-target effects of chemotherapy and direct cancer cells killing. It is recognized as a fruitful strategy to treat and possible to cure cancer. Immunotherapeutic agents are used to activate or boost the activation of the immune system to fight cancer cells through physiological mechanisms often evaded in the offensive march of the disease. These therapeutic strategies have allowed new successes, but also have serious adverse effects including non-specific inflammation and autoimmunity. Sex and gender issues are of primary importance in this field, due to their recognized role in inflammation, immunity and cancer, and the clarification and understanding of these aspects is a necessary step to increase the responses and to diminish the adverse effects of immunotherapy. This review describes the available knowledge on the role of sex and gender in cancer immunotherapy, and will offer insights to stimulate the attention and practice of clinicians and researchers in a gender perspective of new cancer treatment strategies.

Real-life use of denosumab 120 mg every 12 weeks in prolonged treatment over 2 years of patients with breast cancer bone metastases.

PURPOSE: To analyze the activity and safety of denosumab (DNS) 120 mg every 3 months over 2 years of standard treatment (120 mg SC every 4 weeks) of patients with breast cancer bone metastases in real life. METHODS: We prospectively analyzed the activity and safety of denosumab 120 mg every 3 months and 120 mg every 4 weeks in the treatment of 22 patients with breast cancer bone metastases over 2 years of standard treatment. All patients received specific concomitant antineoplastic treatment, chemotherapy or endocrine therapy and/or target therapy. Oral daily calcium (≥500 mg) and vitamin D (≥1000 U) supplement was recommended. RESULTS: Of the 22 patients treated with denosumab, 4 (18.1%) had at least 1 skeletal related event (SRE); 3 (13.6%) had 1 SRE and 1 patient (4.5%) had 2 SRE, all 10% treated with radiotherapy. Overall, no denosumab-related G3 adverse events occurred; in particular, no cases of osteonecrosis of the jaw have been recorded. The decrease in serum calcium levels was mild (G1, 2 patients, 9%), and recovered in a short time (within 2 weeks) with an increase in the oral support of calcium and vitamin D. CONCLUSIONS: Denosumab confirms a good activity profile in terms of delaying and preventing SREs in breast cancer patients and a good safety profile. It represents an optimal treatment resource which doesn't necessitate renal function monitoring and has the convenience of a subcutaneous administration.

Breast cancer patients receiving denosumab during adjuvant aromatase inhibitors treatment: who are the "inadequate responders" patients to denosumab?

PURPOSE: Adjuvant hormone therapy with aromatase inhibitors (AIs) through the induction of tissue hypo-estrogenism induces an increase in osteoclast activity and inhibition of osteoblast activity through the production of RANKL. This is a relevant cause of comorbility in women affected by breast cancer with negative impact on quality of life. We conducted an observational study on patients treated with AIs and denosumab to compare responders and inadequate responders. METHODS: The study design was a historical cohort survey that represented a 42-month follow-up period for patients on hormone treatment with AI for breast cancer and concomitant denosumab (Prolia®) at 60 mg subcutaneously every 6 months. Sixty-eight patients treated consecutively at our Medical Oncology Unit were studied. The comparison was carried out by stratifying on the basis of age, body mass index (BMI), weight, carboxy-terminal collagen crosslink (CTX), lumbar spine and femoral T-scores, FRAX 10-year probability of a fracture, FRAX 10-year probability of a major osteoporotic fracture at baseline and at the end of follow-up. RESULTS: Calculating and comparing the FRAX 10-year probability of hip fragility fracture at baseline in the subgroup of responders and in the inadequate responders subgroup, we found a statistically significant difference (p=0.039). Similarly, a statistically significant difference was found between the two subgroups of patients in terms of FRAX 10-year probability of hip fragility at the end of follow-up (p=0.014) and FRAX 10-year probability of a mayor osteoporotic fracture at the end of follow-up (p=0.043). CONCLUSION: This study suggests the need to control weight in breast cancer survivors and adjuvant AIs treatment in order not only to reduce the incidence of disease relapse but also to safeguard bone health undergoing treatment with denosumab. Indeed, patients tend to respond inadequately to denosumab if they are not careful to control their body weight.

Neuroendocrine Cancer of the Breast: A Rare Entity.

Neuroendocrine breast cancer (NEBC) is a rare histotype of breast carcinoma that presents, in most cases, positive hormone receptors and negative HER2. Indeed, the analysis of gene expression profiles revealed that NEBC belongs mainly to the luminal subtype. Cases of HER2-positive and triple-negative NEBC are rare. The cardinal treatment of early NEBC is surgery, similar to the treatment of invasive non-special histological type carcinoma. The use of radiotherapy follows the criteria applied in infiltrating breast cancer of non-special histotype. In the post-operative phase, therefore after the surgical treatment of mammary quadrantectomy, or mastectomy associated with homolateral sentinel lymph node removal ± axillary dissection, based on the histopathological characteristics of the tumor, the use of chemotherapy (anthracycline + taxane) and/or hormone therapy, whether or not associated with anti-HER2 therapy (trastuzumab) is the rule. Literature data report the use of cisplatin and etoposide, as in small cell lung cancers. Most of the information currently available derive from single case reports or a series of clinical cases; it follows the difficulty of formulating definite recommendations on the correct management of this histological type of breast cancer. This review describes available knowledge on this rare entity to improve the diagnostic and therapeutic strategies and offer insights to stimulate exploration of the many aspects still unknown.

Safe Administration of Ipilimumab, Pembrolizumab, and Nivolumab in a Patient with Metastatic Melanoma, Psoriasis, and a Previous Guillain-Barré Syndrome.

BACKGROUND: Patients with autoimmune diseases were not evaluated in clinical trials with immune checkpoint inhibitors (ICIs), since a history of immune disorders, such as Guillain-Barré syndrome (GBS) and psoriasis, is one of the major risk factors for the development of immune-related adverse events (irAEs). This risk cannot be defined; therefore, physicians are called to manage these patients in clinical practice. CASE REPORT: We report the case of a 62-year-old male patient affected by metastatic melanoma, with a history of GBS and psoriasis, and treated with sequential ipilimumab, pembrolizumab, and nivolumab, without significant toxicities. CONCLUSION: This case report supports that although a history of immune disorders is one of the major risk factors for development of irAEs, in some patients, it could be possible to safely administer sequential treatments with ICIs. A proper decision should be made, considering therapeutic options, disease-related risks, and those related to a recurrence of preexisting autoimmune disorders.

The possible different roles of denosumab in prevention and cure breast cancer bone metastases: A 'hypothesis-generator' study from clinical practice.

The most frequent site of recurrence in breast cancer (BC) is the bone, particularly in patients with 'luminal-like' disease. Denosumab has been shown to prevent aromatase inhibitors (AIs) induced bone resorption in postmenopausal early BC patients and reduce skeletal-related events (SREs) in bone metastatic breast cancer (BMBC). A 'real life' analysis of 90 BMBC patients treated with denosumab was performed. Eighty-six patients (95.6%) had 'luminal-like' disease, 72 (80%) had bone metastases at the time of first recurrence of disease. Among 50 patients with metachronous 'luminal-like' disease, 40 (80%) had first recurrence to the bone. Among these patients median time to skeletal recurrence (TSkR) was shorter for patients who were previously exposed to AIs compared to those who were not (53.0 vs. 102.0 months, respectively; P=0.0300) and longer for patients previously treated with tamoxifen compared to those who were not (102.0 vs. 59.0 months, respectively; P=0.0466). Both of them were not confirmed at multivariate analysis. In the overall population, 17 first SREs were observed (16 radiation therapy) and median time to first SRE was not reached. A statistically significant difference in the incidence of SREs was detected only between patients with exclusively osteolytic bone metastases vs. those without (P=0.013). The presence of exclusively-osteolytic bone metastases was the only factor significantly associated with a shorter time to first SRE (P=0.011). The only G3 toxicity reported was hypocalcemia in one patient. No osteonecrosis of the jaw events (ONJ) occurred. This study demonstrated that a pro-active attitude enables the treatment of the majority of patients with denosumab without significant class-related toxicities. The majority of SREs were from radiation therapy, so pain still remains the clinical hallmark of bone metastases, particularly for osteolytic ones. The suggestion that estrogen deprivation with AIs can favor a 'bone-related' risk conditions for developing bone metastases must be considered with caution and surely needs further validations.

Neoadjuvant chemotherapy in breast cancer: a dose-dense schedule in real life and putative role of PIK3CA mutations.

BACKGROUND: Dose-dense chemotherapy is one of the treatments of choice for neoadjuvant therapy in breast cancer (BC). Activating mutations in PIK3CA gene predict worse response to neoadjuvant chemotherapy for HER2-positive patients, while their role is less clearly defined for HER2-negative tumors. METHODS: We conducted a phase I/II study of neoadjuvant, sequential, dose-dense anthracycline/taxane chemotherapy, plus trastuzumab in HER2-positive patients and investigated the correlation of pre-treatment PIK3CA mutation status with pathologic complete response (pCR) and long-term outcome in a real-life setting. RESULTS: we established a dose-dense docetaxel recommended dose of 60 mg/m2 and 65 mg/m2, with or without trastuzumab, respectively, according to HER2-status, following dose-dense epirubicin-cyclophosphamide (90/600 mg/m2), every 2 weeks. The overall pCR rate was 21.4%; median disease-free survival (DFS) was 52 months and median overall survival (OS) was not yet reached. PIK3CA mutation status was not significantly associated with the pCR rate: 18% for both mutated and wild-type patients. The pCR rate was: 25% in the mutated and 24% in the wild-type (p 0.560) cohort of the HER2-positive subgroup; 33% both in the mutant and wild-type cohort of the triple-negative subgroup; no pCR neither in the mutant nor in the wild-type cohort of the HR-positive/HER2-negative subgroup. Among the HER2-positive population, a trend toward worse DFS was observed in case of mutation, as opposed to the triple negative population. CONCLUSIONS: This study proposes an effective and safe neoadjuvant dose-dense anthracycline/taxane schedule and suggests that PIK3CA mutation analysis can be usefully performed in real-life clinical practice.

Prognostic significance of clinicopathological factors in early breast cancer: 20 years of follow-up in a single-center analysis.

BACKGROUND: To quantify the effect of traditional prognostic factors [nodal status, estrogen-receptor (ER), progesterone-receptor (PR), human epidermal growth factor receptor 2 (HER2)] on long-term outcome of patients with early breast cancer (EBC), treated in clinical practice over a period of about twenty years. RESULTS: 1198 consecutive patients were identified. Median DFS (disease-free survival): ER+/PR±/HER2-, 165 months (mo) if node-negative (N0) and 114mo if node-positive (N+) (p < 0.001); triple-negative (TN), 109mo if N0 and 65mo if N+ (p 0.144); ER+/PR±/HER2+ in patients not-treated with adjuvant trastuzumab (T-), not reached if N0 and 114mo if N+ (p 0.297); ER+/PR±/HER2+ in patients treated with trastuzumab (T+), 95mo if N0 and 85mo if N+ (p 0.615); ER-/PR-/HER2+ T-, not reached if N0 and 26mo if N+ (p 0.279); ER-/PR-/HER2+ T+, not reached if N0 and 66mo if N+ (p 0.014). Median OS (overall survival): ER+/ PR±/HER2-, 166mo if N0 and 144mo if N+ (p 0.028); TN, 158mo if N0 and 96mo if N+ (p 0.384); ER+/PR±/HER2+ T-, not reached if N0 and 157mo if N+ (p 0.475), ER+/PR±/HER2+ T+, not reached if N0 and 106mo if N+ (p 0.436); ER-/PR-/HER2+ T-, not reached if N0 and 34mo if N+ (p 0.273); ER-/PR-/HER2+ T+, not reached neither if N0 nor if N+ (p 0.094). MATERIALS AND METHODS: Disease-free survival (DFS) and overall survival (OS) were evaluated according to tumor characteristics, based on information retrospectively retrieved from patients' medical records. CONCLUSIONS: Pathological tumor characteristics and nodal status still represent useful tools in treatment selection and follow-up decision making of EBC patients in clinical practice.

Bone targeted therapy for preventing skeletal-related events in metastatic breast cancer.

Cancer cells can alter physiological mechanisms within bone resulting in high bone turnover, and consequently in skeletal-related events (SREs), causing severe morbidity in affected patients. The goals of bone targeted therapy, as bisphosphonates and denosumab, are the reduction of incidence and the delay in occurrence of the SREs, to improve quality of life and pain control. The toxicity profile is similar between bisphosphonates and denosumab, even if pyrexia, bone pain, arthralgia, renal failure and hypercalcemia are more common with bisphosphonates, while hypocalcemia and toothache are more frequently reported with denosumab. Osteonecrosis of the jaw (ONJ) occurred infrequently without statistically significant difference. The present review aims to provide an assessment on bone targeted therapies for preventing the occurrence of SREs in bone metastatic breast cancer patients, critically analyzing the evidence available so far on their effectiveness, in light of the different mechanisms of action. Thus, we try to provide tools for the most fitting treatment of bone metastatic breast cancer patients. We also provide an overview on the usefulness of bone turnover markers in clinical practice and new molecules currently under study for the treatment of bone metastatic disease.