A Case of Stage I Vulvar Squamous Cell Carcinoma with Early Relapse and Rapid Disease Progression.

Squamous cell carcinoma (SCC) is the most common subtype of vulvar cancer. Locoregional surgery is often curative when the tumor is diagnosed at an early stage. However, the disease can unexpectedly evolve with a dismal prognosis even after an early diagnosis. We report a case of a woman who experienced a rapid, chemorefractory tumor progression after surgery for stage IB vulvar SCC.

Pancoast's syndrome caused by lymph node metastasis from breast cancer.

Pancoast's syndrome may be the result of neoplastic, inflammatory or infectious disease. We report an unusual case of Pancoast's syndrome in a patient with metastatic breast cancer. A 54-year-old woman, affected by metastatic breast cancer, presented for severe shoulder pain, paraesthesia and numbness in the right arm. Despite further multiple lines of systemic chemotherapy, she developed a progressive enlargement of retropectoral, supraclavicular and infraclavicular lymph node metastases, which involved brachial plexus, apex of lung and anterior mediastinum. Physical examination revealed severe weakness of proximal muscles of the right arm. Neuropathic pain was managed with pharmacological treatment. Lastly, the patient has been treated with intrathecal analgesia with morphine and ziconotide with a good control of pain. The patient died after 3 months.

Skin toxicity evaluation in patients treated with cetuximab for metastatic colorectal cancer: a new tool for more accurate comprehension of quality of life impacts.

OBJECTIVES: The effectiveness of evaluation of the severity of epidermal growth-factor receptor inhibitor (EGFRI)-associated dermatological toxicities remains a topic of debate. This study was designed to assess the correlation between quality of life (QoL) and severity of dermatological toxicity, evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) and our novel scale, the Eruption Scoring System (ESS), in metastatic colorectal cancer (CRC) patients treated with first-line chemotherapy combined with cetuximab. METHODS: Cutaneous toxicity was evaluated, by oncologists and dermatologists, in patients (n=30) with histologically confirmed metastatic CRC who were scheduled to begin first-line chemotherapy combined with the EGFRI, cetuximab, using the NCI-CTCAE and ESS tools. Health-related QoL (HRQoL) was evaluated using the Skindex-29 and Skindex-17 dermatology-specific instruments. Correlations between QoL and skin toxicity severity were assessed using Spearman's rank tests. Interclass correlation coefficients were used to assess interoperator agreement for ESS and NCI-CTCAE v4.0 scoring. RESULTS: A positive correlation was identified between dermatology HRQoL and the severity of dermatological toxicities assessed using the NCI-CTCAE v4.0 scale for cutaneous papulopustular acneiform rash; however, a stronger correlation was observed between HRQoL and toxicities evaluated using the ESS tool. Both NCI-CTCAE v4.0 and ESS tools demonstrated good interobserver agreement for grading of skin toxicity. CONCLUSION: There is a strong correlation between the scores generated by the ESS and NCI-CTCAE tools to grade cutaneous toxicity related to treatment with the anti-EGFR monoclonal antibody, cetuximab. ESS can be considered a valid instrument for identification and grading of the severity of skin toxicity induced by cetuximab, with some advantages over the standard NCI-CTCAE scoring system.

Long-term outcome of breast cancer patients with pathologic N3a lymph node stage.

PURPOSE: To evaluate factors influencing the long-term outcome of patients presenting with 10 or more metastatic axillary lymph nodes (pN3a) after surgery for primary breast cancer. METHOD: Between January 1990 and December 2015, a total of 130 patients with pN3a breast cancer at surgery were identified in our Institutions and included in the study. Twenty-nine of them (22.3%) received neoadjuvant chemotherapy. The Multivariate Cox proportional hazards model was used to determine independent prognostic factors associated with DFS and OS. RESULTS: After a median follow-up of 6.4 years (range 0.87-25 years), 2 patients had a local relapse, 59 distant metastases (1 with local relapse) and 52 patients died. The 5-year DFS and OS rates were 61.8% and 71.5%, respectively. At multivariate analysis, pN3a stage after neoadjuvant chemotherapy (ypN3a) was significantly associated with increased risk of recurrence (HR 1.92, p = 0.02) and death (HR 2.05, p = 0.029). Absence of progesterone receptor (PR) expression was the most important tumor characteristic associated with poor prognosis, both in terms of recurrence (HR 2.55, p < 0.001) and death (HR 2.23, p = 0.019). High levels of Ki-67 index (≥20%) were significantly associated with a shorter OS (HR 2.03, p = 0.027), but not with DFS. CONCLUSIONS: The results of this study indicate that ypN3a stage, lack of expression of PR, and Ki-67 ≥ 20% negatively affect long-term outcome of patients with pN3a breast cancer.

Is the skin a sanctuary for breast cancer cells during treatment with anti-HER2 antibodies?

The occurrence of skin metastases is a common event in patients affected by advanced breast cancer, usually associated with systemic disease progression. Here we describe 2 cases of diffuse cutaneous metastases from HER2-overexpressing breast cancer occurring despite a dramatic response in liver and bone, respectively, during treatment with anti-HER2 antibodies Trastuzumab and Pertuzumab. We discuss the reasons for this discrepancy and suggest a possible implication of impaired immune response in the skin. Future research should provide strategies to overcome the induction of immune privilege in the skin in order to avoid discontinuation of effective treatments.

Effect of targeted agents on the endocrine response of breast cancer in the neoadjuvant setting: a systematic review.

Inhibition of aberrantly activated pathways cross-talking with hormone receptor (HR) improves response to endocrine therapy in patients with HR-positive advanced breast cancer. We performed a Pubmed database systematic review to ascertain the existence of a better clinical response when combining endocrine therapy with targeted agents in the neoadjuvant setting. Preclinical studies or trials evaluating toxicity were excluded. We found nine phase II trials that fulfilled the research criteria. The endocrine agents used were third generation aromatase inhibitors (AIs), anastrozole, letrozole or exemestane. The investigated targeted agents were inhibitors of tyrosine kinase receptors such as gefitinib, imatinib or trastuzumab/lapatinib, inhibitors of mTOR, such as everolimus, inhibitors of COX-2, such as celecoxib, and inhibitors of angiogenesis, such as bevacizumab. The response rate (RR) observed combining endocrine and targeted agents ranged between 36% and 90%. Overall the studies failed to show a remarkable advantage in RR in the combination group compared to historical control subjects receiving AIs alone.

Long-term outcome of neoadjuvant endocrine therapy with aromatase inhibitors in elderly women with hormone receptor-positive breast cancer.

BACKGROUND: Aromatase inhibitors (AIs) are more effective than tamoxifen as neoadjuvant endocrine therapy (NET) for hormone receptor (HR)-positive breast cancer. Here we report the surgical and long-term outcome of elderly postmenopausal patients with locally advanced, HR-positive breast cancer treated with preoperative AIs. METHODS: Between January 2003 and December 2012, 144 postmenopausal patients inoperable with breast conservative surgery (BCS) received letrozole, anastrozole, or exemestane as NET. Patients underwent breast surgery and received adjuvant AIs. Adjuvant systemic therapy, chemotherapy and/or trastuzumab, and adjuvant radiotherapy were administered as appropriate, but limited to high-risk patients with few or no comorbidities. RESULTS: After a median follow-up of 49 months, 4 (3.0 %) patients had local relapse, 18 (12.5 %) had distant metastases, and 24 (17.0 %) died. BCS was performed in 121 (84.0 %) patients. A tumor size <3 cm and human epidermal growth factor receptor 2 (HER2) negativity were predictors of BCS. The achievement of BCS and grade G1 were significantly associated with longer disease-free survival (DFS) (p = 0.009 and p = 0.01, respectively) and overall survival (p = 0.002 and p = 0.005, respectively). Residual tumor ≤2 cm (yT0-yT1) in the longest diameter after NET was also statistically associated with longer DFS (p = 0.005). CONCLUSIONS: The results of this retrospective study indicate that elderly breast cancer patients with a tumor size <3 cm at diagnosis and HER2 negativity have a higher probability of achieving BCS after NET. Moreover, patients treated with BCS and with grade G1 tumor have a reduced risk of recurrence and death in the long-term follow-up.

Role of Hydroxamate-Based Histone Deacetylase Inhibitors (Hb-HDACIs) in the Treatment of Solid Malignancies.

Hydroxamate-based histone deacetylase inhibitors (Hb-HDACIs), such as vorinostat, belinostat and panobinostat, have been previously shown to have a wide range of activity in hematologic malignancies such as cutaneous T-cell lymphoma and multiple myeloma. Recent data show that they synergize with a variety of cytotoxic and molecular targeted agents in many different solid tumors, including breast, prostate, pancreatic, lung and ovarian cancer. Hb-HDACIs have a quite good toxicity profile and are now being tested in phase I and II clinical trials in solid tumors with promising results in selected neoplasms, such as hepatocarcinoma. This review will focus on their clinical activity and safety in patients with advanced solid neoplasms.

Long-term outcome of neoadjuvant systemic therapy for locally advanced breast cancer in routine clinical practice.

PURPOSE: The aim of this study is to evaluate the long-term outcome of patients with locally advanced breast cancer treated with neoadjuvant systemic chemotherapy (NST) in routine clinical practice. METHODS: Four hundred and nine patients were identified between January 1999 and December 2011. All patients received NST followed by surgery, adjuvant treatments and radiotherapy, as appropriate. RESULTS: At Kaplan-Meier analysis, patients with surgical stage III disease were more likely to develop distant metastasis and die from breast cancer (p < 0.001). Luminal A and luminal B/HER2-negative patients had better prognosis; moreover, patients with hormone receptor (HR)-positive tumors had a significantly longer DRFS (p < 0.0049) and OS (p < 0.0001) compared with patients with HR-negative tumors as well as patients who underwent breast-conserving surgery (DRFS and OS: p < 0.001). In multivariate analysis, HR negativity (p < 0.001 for both DRFS and OS), mastectomy (DRFS: p = 0.009; OS: p = 0.05) and stage III disease (DRFS: p < 0.001; OS: p = 0.003) were associated with shorter DRFS and OS. CONCLUSIONS: HR negativity, mastectomy and pathological stage III disease are the variables independently associated with a worse outcome in our cohort of patients. These data are of high interest since they derive from a very heterogeneous group of patients, treated with different neoadjuvant/adjuvant regimens outside of clinical trials and with a long follow-up period.

An epigenetic approach to pancreatic cancer treatment: the prospective role of histone deacetylase inhibitors.

Pancreatic ductal adenocarcinoma (PDAC) is quite resistant to conventional treatments, and gemcitabine, the standard chemotherapeutic agent, offers only a small benefit. Development and progression of PDAC are complex processes involving dysregulation of multiple signal transduction pathways arising from not only genetic but also epigenetic alterations. This makes the epigenetic approach to the treatment of PDAC of great interest. Histone deacetylases, a family of enzymes that, by removal of acetyl groups from a variety of histone and nonhistone proteins, play an important role in the epigenetic regulation of gene expression, are frequently dysregulated in PDAC. In particular, overexpression of class I histone deacetylases has been related to higher tumor grade, poor prognosis and development of chemoresistance. Histone deacetylase inhibitors (HDACIs), a novel class of agents endowed with pleiotropic antitumor effects, appear promising either for their preferential toxicity towards transformed as compared to normal cells and their ability to synergistically enhance the anticancer activity of radiotherapy and many chemotherapeutic agents. Many HDACIs have been shown to increase the antiproliferative and proapoptotic effects of gemcitabine, 5-fluorouracil and bortezomib, a new proteasome inhibitor, in vitro and in vivo PDAC xenograft models. MGCD0103, romidepsin, panobinostat, vorinostat and valproic acid, are currently being tested in association with radiotherapy or chemotherapy (gemcitabine, fluoropyrimidines, proteasome inhibitors) in phase I-II clinical trials in patients with locally advanced or metastatic PDAC.

Molecular mechanisms of endocrine resistance and their implication in the therapy of breast cancer.

The use of endocrine agents is a safe and effective treatment in the management of hormone-sensitive breast cancer. Unfortunately, sooner or later, tumor cells develop resistance to endocrine manipulation making useless this approach. During the last decade, new molecules and intracellular signaling pathways involved in endocrine resistance have been identified. Several studies have documented that estrogen receptor signaling may maintain a pivotal role in the tumor growth despite the failure of a previous hormonal treatment. In this review we will discuss the general principles for optimizing the choice of endocrine therapy based on an understanding of the molecular mechanisms responsible for resistance to the different anti-hormonal agents.