Role of innate and adaptive immunity in the efficacy of anti-HER2 monoclonal antibodies for HER2-positive breast cancer.

Anti-HER2 monoclonal antibodies (mAbs) such as trastuzumab are effective for all stages of HER2-positive breast cancer (BC). However, intrinsic or acquired resistance to these drugs may occur in a significant number of patients (pts) and, except for HER2 status, no validated predictive factors of response/resistance have been identified to date. This lack is in part due to the not yet fully elucidated mechanism of action of mAbs in vivo. Increasing evidence suggests a significant contribution of both innate and adaptive immunity to the antitumor effects of mAbs. The aim of this review was to describe the role of innate and adaptive immunity in the efficacy of anti-HER2 mAbs and to report known and novel strategies to be used for optimizing immune effects of anti-HER2 therapies for HER2-positive BC.

Could gonadotropin-releasing hormone analogs be helpful in the treatment of triple-negative breast cancer?

AIM: Treatment of triple-negative breast cancer (TNBC) imposes great challenges, due to a lack of molecular targets. While use of gonadotropin-releasing hormone (GnRH) analogs has been validated in ER-positive breast cancer, this option has not been investigated in TNBC, even though a significant portion of these tumors upregulate GnRH receptors. We performed a meta-analysis of the literature to evaluate the effect of GnRH analogs in TNBC. METHODS: Four studies were included in this study. RESULTS: We detected a non-significant improvement in overall survival with GnRH analogs, while progression-free survival was unchanged. DISCUSSION: The majority of the trials evaluated in this analysis were designed to test efficacy of GnRH analogs in preventing premature ovarian failure. This may represent a limitation of our study as these trials were not specifically designed to detect differences in survival outcome measures. CONCLUSION: Our results suggest that GnRH analogs may be useful as a targeted therapy in TNBC. Randomized prospective clinical trials are needed to investigate this hypothesis in the clinic.

Triple negative status and BRCA mutations in contralateral breast cancer: a population-based study.

BACKGROUND AND AIM OF THE WORK: BRCA1/2 mutation carriers diagnosed with breast cancer have a strong life-time risk of developing contralateral breast cancer (CBC). We performed a population-based study with the aim of estimating the proportion of CBC associated with BRCA1/BRCA2 mutations, and the contribution of germline mutations to both molecular and clinical features of these tumors. METHODS: Fifty-five women with invasive CBC consecutively seen at the at the Genetic Oncology Service of the University Hospital of Parma from 2000 to 2011 were subjected to BRCA1/2 testing. Fifty-five case-matched, unilateral breast cancer (UBC)  patients (pts), which tested negative for BRCA1/2 mutations, were selected as control group. RESULTS: BRCA mutations were detected in 13 (24%) of 55 CBC pts. Women with BRCA1 mutations, and to a lesser extent BRCA2 mutations, were significantly more likely to present with high histologic grade, negative hormone receptor status and high proliferation rate in both first and second primary breast cancers than BRCA-negative, CBC tumors. A diagnosis of triple-negative breast cancer (TNBC) was significantly more frequent in women with BRCA mutations in comparison with BRCA-negative, UBC controls. There were no survival differences between BRCA-positive and non-BRCA tumors. CONCLUSIONS: Results of the present study indicate that both first primary and second primary breast cancers in BRCA carriers are qualitatively distinct from BRCA negative CBC, and from sporadic UBC controls. These findings highlight relevant clinical considerations about the potential value of BRCA testing in women with CBC as well as therapeutic, preventive, and surveillance implications for patients carrying a mutation.

ALK and ROS1 rearrangements tested by fluorescence in situ hybridization in cytological smears from advanced non-small cell lung cancer patients.

BACKGROUND: The identification of ALK and ROS1 rearrangements and the availability of an effective target therapy, such as crizotinib, represent a new option in the treatment of advanced non-small cell lung cancer (NSCLC) patients. In light of recent advances in non-invasive diagnostic procedures, we aimed to demonstrate that direct cytological smears are suitable for assessing ALK and ROS1 rearrangements in patients with NSCLC. METHODS: Fifty-five patients with a cytological diagnosis of lung adenocarcinoma (ADC) were evaluated for ALK rearrangements by fluorescence in situ hybridization (FISH) and 12 patients for ROS1 FISH rearrangements. Seventeen of the 55 cytological samples tested for ALK were obtained from the primary tumor and 38 from metastatic lesions. Ten of 12 samples evaluated for ROS1 were obtained from metastatic sites and two from the primary tumor. RESULTS: ALK FISH was successful in 49/55 (89%) cytological ADC samples and ROS1 FISH in all 12 cytological samples. ALK rearrangements were found in 3/13 (23%) primary tumors and 7/36 (19%) metastatic sites. ROS1 rearrangements were found in one of the two primary tumors and in two of the 10 metastases. Two of the three rearranged cases were tested on cytology after knowing that they were rearranged on histology in order to increase representativeness of ROS1 rearranged cases in this study. CONCLUSION: Whenever cytology represents the only available material for diagnosis and biological characterization of NSCLC, minimally invasive procedures may provide an additional important source of cellular material for FISH assessment of ALK and ROS1 rearrangements.

Retroperitoneal cystoadenocarcinoma: a case report with a literature review.

Primary retroperitoneal mucinous cystoadenocarcinoma (PRMC) is an extremely rare clinical entity with about 50 cases described by the literature. Given the rarity of this pathology, the sharing of accurate available informations is  important to  improve its knowledge. We reported a case of a woman diagnosed with PRMC who received different lines of chemotherapy and radiotherapy and we also performed a review of the literature on the issue. (www.actabiomedica.it).

Prognostic and predictive factors in patients treated with chemotherapy for advanced urothelial cancer: where do we stand?

The standard of care for patients with local advanced or metastatic urothelial carcinoma is chemotherapy. However, results with this are rather disappointing, and validated prognostic factors and biomarkers of tumor response, which are useful in the decision-making process, are still lacking. PubMed databases were searched for articles published until November 2013. Several promising clinical and biological candidate prognostic factors or markers of tumor response to first- or second-line therapy, such as hemoglobin, performance status, visceral metastasis and ERCC1, hENT1 and EMT markers, have been identified and described in this article. In summary, clinical parameters and molecular profiling could revolutionize the management of local advanced or metastatic urothelial cancer, but an improvement in individualized therapeutic approaches still seems distant.

Palliative care and end-stage colorectal cancer management: the surgeon meets the oncologist.

Colorectal cancer (CRC) is a common neoplasia in the Western countries, with considerable morbidity and mortality. Every fifth patient with CRC presents with metastatic disease, which is not curable with radical intent in roughly 80% of cases. Traditionally approached surgically, by resection of the primitive tumor or stoma, the management to incurable stage IV CRC patients has significantly changed over the last three decades and is nowadays multidisciplinary, with a pivotal role played by chemotherapy (CHT). This latter have allowed for a dramatic increase in survival, whereas the role of colonic and liver surgery is nowadays matter of debate. Although any generalization is difficult, two main situations are considered, asymptomatic (or minimally symptomatic) and severely symptomatic patients needing aggressive management, including emergency cases. In asymptomatic patients, new CHT regimens allow today long survival in selected patients, also exceeding two years. The role of colonic resection in this group has been challenged in recent years, as it is not clear whether the resection of primary CRC may imply a further increase in survival, thus justifying surgery-related morbidity/mortality in such a class of short-living patients. Secondary surgery of liver metastasis is gaining acceptance since, under new generation CHT regimens, an increasing amount of patients with distant metastasis initially considered non resectable become resectable, with a significant increase in long term survival. The management of CRC emergency patients still represents a major issue in Western countries, and is associated to high morbidity/mortality. Obstruction is traditionally approached surgically by colonic resection, stoma or internal by-pass, although nowadays CRC stenting is a feasible option. Nevertheless, CRC stent has peculiar contraindications and complications, and its long-term cost-effectiveness is questionable, especially in the light of recently increased survival. Perforation is associated with the highest mortality and remains mostly matter for surgeons, by abdominal lavage/drainage, colonic resection and/or stoma. Bleeding and other CRC-related symptoms (pain, tenesmus, etc.) may be managed by several mini-invasive approaches, including radiotherapy, laser therapy and other transanal procedures.

Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study.

BACKGROUND: A series of retrospective studies have reported that patients with human epidermal growth factor receptor 2(HER2)-positive breast cancer are at a greater risk of central nervous system (CNS) metastases. Trastuzumab, which does not cross the blood-brain barrier, has been associated with this increased risk. METHODS: The authors evaluated incidence, survival, and risk factors for CNS metastases in the incident breast cancer population systematically collected by the Parma Province Cancer Registry over the 4-year period between 2004 and 2007. RESULTS: A total of 1458 patients with a diagnosis of stage I to III invasive breast cancer were analyzed for study purposes. At a median follow-up of 4.1 years, CNS events were observed in 1.3% and 5% of HER2-negative patients and HER2-positive patients, respectively (P < .0001). The administration of trastuzumab either as adjuvant therapy or for metastatic disease was associated with a significantly increased risk of CNS involvement at first disease recurrence and after first extracranial recurrence, respectively. According to multivariate analysis, HER2-positive status and trastuzumab treatment, high Ki-67 index, and hormone receptor negativity remained independent risk factors for the development of CNS metastasis. CONCLUSIONS: To the authors' knowledge, this is the first population-based cancer registry study analyzing factors associated with CNS recurrence in a general population of newly diagnosed breast cancer patients with known HER2 status. The data from the current study provide evidence that patients with HER2-positive breast cancer have a significantly higher incidence of CNS metastasis after treatment with trastuzumab. Improvements in systemic control and overall survival associated with trastuzumab-based therapy may lead to an "unmasking" of CNS disease recurrence that would otherwise remain clinically silent before a patient's death.