HER2 and central nervous system metastasis in patients with breast cancer

We report a case of a patient who developed a central nervous system (CNS) metastasis 17 months after surgery and adjuvant therapy for stage II breast cancer. The HER2 status of the primary tumor as determined by immunohistochemistry (IHC) was 1+, and fluorescence in situ hybridization (FISH) performed retrospectively showed a borderline-negative result (ratio, 1:9), although HER2 amplification was present in a minority of breast cancer cells. By contrast, the HER2 status of the CNS metastasis was positive by IHC (3+) and FISH (ratio, 3:7). This report discusses the possibility that, for metastatic invasion into the CNS, clonal selection may occur, favoring HER2-positive cell clones.     

Risk factors for central nervous system metastasis in patients with metastatic breast cancer

Aims Patients with metastatic breast cancer (MBC) and central nervous system (CNS) involvement have an impaired survival and quality of life. In this study, we investigated the risk factors for CNS metastasis among patients with MBC. Methods The risk factors for development of CNS metastasis were analyzed in 154 patients with MBC. Expression of c-erbB-2, Ki-67, p53, and hormone receptors was examined by immunohistochemistry (IHC) in breast cancer tissue samples from the 154 patients. Kaplan-Meier and log-rank tests were used for the analysis of overall survival (OS). Chi-square test was used for univariate analysis. Results Median OS was significantly poorer for patients with CNS metastasis as compared with patients with no CNS metastasis (OS, 23 mo vs 30 mo, respectively;p = 0.03). Ki-67 and p53 overexpressions by IHC, and lung metastasis as the first site of relapse, were associated with a higher risk of developing CNS metastasis in the univariate analysis (p ≤ 0.05). The presence of lung metastasis (odds ratio [OR]= 2.82, 95% confidence interval [CI]: 1.13-7.00,p = 0.02) and p53 overexpression (OR = 2.44, 95% CI: 0.99-6.00,p = 0.05) were the two predictive factors associated with occurrence of CNS metastasis in the multivariate analysis. Conclusions In this study, the presences of lung metastasis as the first site of relapse and p53 overexpression were predictive for the occurrence of CNS metastasis in patients with MBC. Life expectancy of patients with CNS metastasis is significantly shorter than those without CNS metastasis. These results may have clinical significance in counseling MBC patients with regard to their prognosis.     

Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis

BACKGROUND: Breast cancer is the second most common cause of central nervous system (CNS) metastases. Several risk factors for CNS metastases have been reported. The objective of the current study was to describe clinicopathologic characteristics and prognostic factors in breast cancer patients with CNS metastases. METHODS: The authors retrospectively evaluated clinical data from 420 patients who had been diagnosed with breast cancer and CNS metastasis between 1994 and 2004 at the University of Texas M. D. Anderson Cancer Center. RESULTS: The median age of the patients at the time of diagnosis of breast cancer was 45 years (range, 25-77 years). Premenopausal and postmenopausal patients were distributed equally. Most patients had invasive ductal histology (91.2%), grade 3 tumors (81.4%) (using the modified Black nuclear grading system), T2 tumor classification (40.1%), and N1 lymph node status (59.7%) diagnosis. Forty percent of patients had estrogen receptor (ER)-positive disease, and 34% had progesterone receptor-positive disease. HER-2/neu status was recorded for only 248 patients, and 39% of the patients in that group had HER-2/neu-positive disease. The most common sites of first metastasis were liver, bone, and lung. CNS metastasis was the site of first recurrence in 53 patients (12%). In total, 329 patients had received either neoadjuvant treatment (113 patients) or adjuvant chemotherapy (216 patients). The majority of those patients (74.4%) had received anthracycline-based regimens. Metastasis was solitary in 111 patients (26.4%), and 29 patients had only leptomeningeal metastases. The median time from breast cancer diagnosis to CNS metastasis was 30.9 months (range, from -5 months to 216.7 months). The median follow-up after a diagnosis of CNS metastasis was 6 months (range, 7-95.9 months). In all, 359 patients died, and the overall median survival was 6.8 months. Only age at diagnosis and ER status were associated significantly with overall survival in the multivariate analysis. CONCLUSIONS: The current results indicated that the prognosis remains patients with breast cancer metastatic to the CNS. More effective treatment approaches are needed for patients with CNS metastases, even for those with favorable prognostic factors, such as ER-positive tumors or younger age.     

乳腺癌抗血管生成治疗:现状与前景

Tumor angiogenesis plays an important role in the growth, invasion and metastasis of breast cancer, therefore re-cently a very active area of breast cancer research involves the addition of antiangiogenic therapy. Numerous clinical studies for several antiangiogenic agents have recently been conducted in breast cancer patients and have shown clinically significant improvement in outcomes. This review gives a brief background to breast cancer angiogenesis, also focusing on current prog-ress in the field of a...     

Infertility and pregnancy after breast cancer: current knowledge and future perspectives

Fertility impairment induced by adjuvant treatments and potential risk associated with pregnancy, are major concerns of young pre-menopausal patients with early breast cancer. Although current evidences suggest that pregnancy does not negatively affect prognosis, a low rate (3-8%) of pregnancy after breast cancer has been reported. Among the potential causes of such a low rate there are a high chance of spontaneous abortions (25%) as well as the fertility impairment induced by adjuvant treatments. No standard strategy to preserve fertility in breast cancer patients is available so far. Experimental approaches include cryopreservation strategies, and use of gonadotropin-releasing hormone (GnRH) agonists to render germinal epithelium quiescent and less sensitive to the chemotherapy cytotoxicity. Here, we reviewed current knowledge about incidence and risks of pregnancy after breast cancer, risks of ovarian failure after adjuvant treatments and experimental strategies aiming to preserve ovarian function and fertility in young breast cancer patients.     

Immunotherapy and immunobiomarker in breast cancer: current practice and future perspectives

Among the new cancer cases and resulting deaths among women worldwide, breast cancer is the most significant threat to women’s health. In recent years, immunotherapy was initially used to treat patients with metastatic breast cancer, where it demonstrated its unique value by providing a novel way to improve therapeutic effects and prolong survival time. With the development of clinical trials related to immunotherapy for breast cancer, tumour vaccines, such as DNA vaccines, have been observed to improve the disease-free survival (DFS) and overall survival (OS) of patients. Monoclonal antibodies have also shown good efficacy, and adoptive cell therapies, such as CAR-T, exhibit strong tumour killing ability and good safety, and thus, these therapies may comprise a new strategy for the treatment of breast cancer. These breakthrough successes have promoted the achievement of “individualized” breast cancer treatment. Moreover, a recent study showed that patients with various cancer types with a higher tumour mutational burden (TMB) are more likely to benefit from immunotherapy. As research progresses, TMB may also demonstrate a certain clinical significance in the treatment of breast cancer. This paper reviews the latest research progress on breast cancer immunotherapy and the predictive value and application status of TMB in immunotherapy regimens for breast cancer patients to provide a reference for further in-depth studies of breast cancer immunotherapy.     

Local and systemic therapy in breast cancer patients with central nervous system metastases

Purpose

As survival of patients with central nervous system (CNS) metastases from breast cancer is poor and incidence rates are increasing, there is a growing need for better treatment strategies. In the current study, the efficacy of local and systemic therapies was analyzed in breast cancer patients with CNS metastases.

Methods

Medical records from breast cancer patients with brain and/or leptomeningeal metastases (LM) treated at a tertiary referral center and a teaching hospital between 2010 and 2020 were retrospectively studied. Main outcomes of interest were overall survival (OS) and CNS progression free survival. Analyses were performed among patients with brain metastases (BM) and patients with LM, for the different systemic and local therapies for CNS metastases, and for subgroups based on breast cancer subtypes.

Results

We identified 155 patients, 97 with BM and 58 with LM. Median OS was 15.9 months for patients with BM and 1.5 months for patients with LM. Median OS was significantly longer for HER2-positive patients with BM (22.8 months) vs triple negative (8.4 months) and hormone receptor positive/HER2-negative (5.9 months) (P?<?0.001). Patients with BM receiving both local and systemic therapy also had a longer median OS (21.8 months), compared to the other three subgroups (local therapy only: 9.9 months, systemic therapy only: 4.3 months, no therapy: 0.5 months, P?<?0.001). No significant difference in OS was observed between different systemic treatment regimens.

Conclusion

Breast cancer patients with BM show longest median OS when the subtype is HER2-positive and when they are treated with both local and systemic therapy.

     

Survival of breast cancer patients with synchronous or metachronous central nervous system metastases

BackgroundCentral nervous system (CNS) metastases represent a devastating complication for advanced breast cancer patients. This observational study examines the influence of patient, tumour and treatment characteristics on overall survival after synchronous or metachronous CNS metastases.MethodsInformation on 992 breast cancer patients with CNS metastases (whose primary tumour was diagnosed between 2004 and 2010) was retrieved from the Netherlands Cancer Registry (NCR). Overall survival was calculated from the date of CNS metastatic diagnosis, and the impact of prognostic factors on survival was assessed using univariate and multivariate extended Cox-regression models.ResultsWe identified 165 patients with synchronous and 827 patients with metachronous CNS metastases. The majority of patients (88%) presented with brain metastases only, 12% had leptomeningeal metastases. Overall median survival was 5.0 months. Non-triple-negative breast cancer and systemic therapy were associated with improved survival in both groups. In patients with synchronous CNS metastases, surgery for the primary tumour and the metastases also improved survival. In patients with metachronous metastases, younger age (<50 years), lower initial tumour stage (I), ductal carcinoma, a prolonged time interval until diagnosis of CNS metastasis (>1 year), and absence of extracranial metastases were associated with improved survival. Metastasectomy and radiation therapy did not provide benefit beyond the first six months.ConclusionsNo difference in survival was established between synchronous and metachronous CNS metastases. Triple-negative disease is prognostically unfavourable in both groups, while those receiving treatment have a better outcome. Metastasectomy and radiotherapy improve survival within the first six months, and additional benefit may be derived from systemic therapy.     

Treatment of HER2-positive breast cancer: current status and future perspectives

The advent of HER2-directed therapies has significantly improved the outlook for patients with HER2-positive early stage breast cancer. However, a significant proportion of these patients still relapse and die of breast cancer. Trials to define, refine and optimize the use of the two approved HER2-targeted agents (trastuzumab and lapatinib) in patients with HER2-positive early stage breast cancer are ongoing. In addition, promising new approaches are being developed including monoclonal antibodies and small-molecule tyrosine kinase inhibitors targeting HER2 or other HER family members, antibodies linked to cytotoxic moieties or modified to improve their immunological function, immunostimulatory peptides, and targeting the PI3K and IGF-1R pathways. Improved understanding of the HER2 signaling pathway, its relationship with other signaling pathways and mechanisms of resistance has also led to the development of rational combination therapies and to a greater insight into treatment response in patients with HER2-positive breast cancer. Based on promising results with new agents in HER2-positive advanced-stage disease, a series of large trials in the adjuvant and neoadjuvant settings are planned or ongoing. This Review focuses on current treatment for patients with HER2-positive breast cancer and aims to update practicing clinicians on likely future developments in the treatment for this disease according to ongoing clinical trials and translational research.     

Meeting report: primary central nervous system lymphoma: standards of care and future perspectives

A standard of care for patients with primary central nervous system lymphoma (PCNSL) has not been defined. Current controversies concern, amongst others, the role, dose and timing of radiotherapy, the role of intrathecal chemotherapy and the delineation of age-specific standards of care. Given the strong clinical trial activities for PCNSL in Germany, the PCNSL conference held in Tubingen aimed at comparing the diverging trial strategies in Germany and at exploring the options for joint activities of the various PCNSL study groups in the near future.     

Breast cancer bone metastasis and current small therapeutics

Patients with advanced breast cancer frequently develop metastasis to bone. Bone metastasis results in intractable pain and a high risk of fractures due to tumor-driven bone loss (osteolysis), which is caused by increased osteoclast activity. Osteolysis releases bone-bound growth factors including transforming growth factor beta (TGF-β). The widely accepted model of osteolytic bone metastasis in breast cancer is based on the hypothesis that the TGF-β released during osteolytic lesion development stimulates tumor cell parathyroid hormone related protein (PTHrP), causing stromal cells to secrete receptor activator of NFκB ligand (RANKL), thus increasing osteoclast differentiation. Elevated osteoclast numbers results in increased bone resorption, leading to more TGF-β being released from bone. This interaction between tumor cells and the bone microenvironment results in a vicious cycle of bone destruction and tumor growth. Bisphosphonates are commonly prescribed small molecule therapeutics that target tumor-driven osteoclastic activity in osteolytic breast cancers. In addition to bisphosphonate therapies, steroidal and non-steroidal antiestrogen and adjuvant therapies with aromatase inhibitors are additional small molecule therapies that may add to the arsenal for treatment of osteolytic breast cancer. This review focuses on a brief discussion of tumor-driven osteolysis and the effects of small molecule therapies in reducing osteolytic tumor progression.     

Primary breast cancer phenotypes associated with propensity for central nervous system metastases

BACKGROUND: There is anecdotal evidence that the incidence of central nervous system (CNS) metastases in breast cancer patients is increasing. It is unclear whether specific tumor biological properties or the use of systemic therapies influence this risk. METHODS: Using a database of 10,782 patients, 2685 patients were identified who experienced recurrence distantly. Clinical and biological features were analyzed in 2 ways: (1) patients who ever had versus those who never had CNS metastases, and (2) CNS metastases as the first site of recurrence versus those who had other sites. Correlations of survival after CNS metastasis with clinical and biologic features were also analyzed. RESULTS: In the ever versus never analysis, CNS metastases were significantly associated with younger age, premenopausal status, infiltrating ductal carcinoma histology (IDC), estrogen receptor (ER) and progesterone receptor (PR) negativity, low Bcl-2, high S-phase, aneuploidy, and altered p53. Tumor size, lymph node status, and use of adjuvant systemic therapy played little role. HER-2 overexpression was not associated with an increased risk in these patients (none of whom were treated with trastuzumab) (P = .91). However, epidermal growth factor receptor (EGFR) overexpression was associated with increased risk (P = .02). A multivariate analysis revealed ER negativity (odds ratio [OR] 2.8, P < .001), IDC histology (OR 2.5, P = .02), and young age (P < .001) as independent factors for CNS metastases. The clinical and biologic profiles of primary tumors with CNS metastases at first recurrence did not differ from those with CNS metastases after recurrence to other sites, except for HER-2 status. HER-2-positive tumors were not more likely to undergo recurrence initially in the CNS (P =.04). The median survival after CNS metastases was 5.5 months and HER-2-positive patients had a shorter survival. CONCLUSIONS: Younger patients with hormone receptor-negative, highly proliferative, genomically unstable, and p53-altered tumors were at increased relative risk for CNS metastases. HER-2 expression and adjuvant systemic therapies did not increase this risk.     

Metastatic soft tissue sarcoma: current treatment landscape and future perspectives

Introduction: The therapeutic armamentarium for advanced soft tissue sarcoma (STS) has increased over the last few years. Doxorubicin monotherapy or in combination is now the established first line treatment. Beyond first line treatment, no standard therapy has been established. Novel drugs have reached the late-clinical stage development demonstrating to be effective in controlled studies. While these novel treatments can be beneficial to a subset of patients, even producing long lasting remissions, a significant fraction of the STS population derives limited benefit. This is due to the fact that STS is a very heterogeneous disease with different histopathologic features, biological characteristics and clinical behaviour.

Areas covered: The primary aim of this review is to summarize data from recent phase III clinical trials in unselected STS population, and to discuss their impact on the current clinical practice. Phase I-II trials of special interest are discussed as well.

Expert commentary: Although our efforts in this research task are ongoing, the integration of biological therapies, the anti-angiogenesis targeted treatments as well as immunotherapy that may further improve the long term control of advanced STS are of special clinical interest. Clinical management of advanced STS should be tailored to each patient in order to optimize therapy.     

Targeted and immuno-biology driven treatment strategies for triple-negative breast cancer: current knowledge and future perspectives

Introduction: Accounting for about 15% of breast cancer patients, triple-negative breast cancer (TNBC) is responsible for 25% of disease related deaths, more frequent distant spread and visceral metastasis. However, improving survival in TNBC failed and primary resistance, immunological ignorance and tumor heterogeneity limit clinical activity of novel therapies. In view of recent molecular, genetic and immunologic insights, this review aims to describe the current status of immunological and targeted treatments from a hypothesis driven perspective.

Areas covered: Recent preclinical studies and ongoing clinical trials for immune directed and targeted treatments of TNBC are summarized, including immune-checkpoint blockade, resistance mechanisms, inhibition of poly (ADP-ribose) polymerase (PARP), combinatorial strategies as well as preclinical, hypothesis generating studies.

Expert commentary: Sustained responses have been observed with immune-checkpoint blockade and PARP inhibitors demonstrated remarkable efficacy in germline BRCA mutated TNBC. In order to generate clinical success of many other, to date ineffective, targeted and immune therapies, the integration of multidimensional, large amounts of data, will be essential and likely accelerate treatment progress of TNBC.     

The clinical development of vaccines for HER2+ breast cancer: Current landscape and future perspectives

Human epidermal growth factor receptor 2 (HER2) is a tumor associated antigen over-expressed in 20–30% of cases of breast cancer. Passive immune therapy with HER2-directed monoclonal antibodies (mabs) has changed the natural history of this subset of breast tumors both in the localized and metastatic settings. The safety and efficacy of HER2 vaccines have been assessed in early phase clinical trials but to date clinically relevant results in late phase trials remain an elusive target. Here, we review the recent translational discoveries related to the interactions between the adaptive immune system and the HER2 antigen in breast cancer, results of published clinical trials, and future directions in the field of HER2 vaccine treatment development.     

PET in the diagnosis and management of patients with brain metastasis: current role and future perspectives

Systemic cancer is the second most common cause of death in developed countries and metastatic brain tumour the most common tumour of the central nervous system (CNS). As the incidence of brain metastases appears to be rising, more accurate non-invasive imaging modalities for diagnosis, prognosis, prediction and follow-up of treatment are requisites for efficient patient management. Positron emission tomography (PET) imaging has the ability to evaluate different aspects of tumour microenvironment on the molecular and cellular level and impact the workup of patients with brain metastasis. This article reviews the current application of PET imaging in patients with metastatic brain disease.     

Active immunotherapy in HER2 overexpressing breast cancer: current status and future perspectives

BackgroundThe use of anti-HER2 monoclonal antibodies (mAbs) has improved the clinical outcome of HER2-overexpressing breast cancers (BCs). Unfortunately, often these tumors tend to relapse and, when metastatic, the duration of clinical benefit is limited over time and almost invariably followed by tumor progression. Alternative approaches to this essentially passive immunotherapy are therefore needed in HER2-overexpressing BC patients. As HER2 is one of the most suitable targets for active immunotherapy in BC, manipulating the immune system is a highly attractive approach.Material and methodsA computer-based literature search was carried out using PubMed (keywords: breast neoplasm, HER2 vaccine, immunology); data reported at international meetings were included.ResultsThis review provides a focus on the following active vaccinal approaches under clinical investigation against HER2-overexpressing BC: (i) peptide and protein based; (ii) DNA based; (iii) whole tumor cell based; (iv) dendritic cell based. Moreover, the review discuss future challenges in the field, trying to define the best setting for the development of this innovative strategy, considering both immunological and clinical aspects of HER2 targeting.ConclusionsDevelopment of effective vaccines for BC remains a distinct challenge but is likely to become a substantial advance for patients with HER2-overexpressing BCs.