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15 pages, 3786 KiB

Open AccessArticle

Prediction of Short and Long Survival after Surgery for Breast Cancer Brain Metastases

by Anna Michel, Marvin Darkwah Oppong, Laurèl Rauschenbach, Thiemo Florin Dinger, Lennart Barthel, Daniela Pierscianek, Karsten H. Wrede, Jörg Hense, Christoph Pöttgen, Andreas Junker, Teresa Schmidt, Antonella Iannaccone, Rainer Kimmig, Ulrich Sure and Ramazan Jabbarli

Cancers 2022, 14(6), 1437; https://doi.org/10.3390/cancers14061437 - 10 Mar 2022

Viewed by 1757

Abstract

Background: Brain metastases requiring surgical treatment determine the prognosis of patients with breast cancer. We aimed to develop the scores for the prediction of short (<6 months) and long (≥3 years) survival after BCBM surgery. Methods: Female patients with BCBM surgery between 2008 [...] Read more.

Background: Brain metastases requiring surgical treatment determine the prognosis of patients with breast cancer. We aimed to develop the scores for the prediction of short (<6 months) and long (≥3 years) survival after BCBM surgery. Methods: Female patients with BCBM surgery between 2008 and 2019 were included. The new scores were constructed upon independent predictors for short and long postoperative survival. Results: In the final cohort (n = 95), 18 (18.9%) and 22 (23.2%) patients experienced short and long postoperative survival, respectively. Breast-preserving surgery, presence of multiple brain metastases and age ≥ 65 years at breast cancer diagnosis were identified as independent predictors of short postoperative survival. In turn, positive HER2 receptor status in brain metastases, time interval ≥ 3 years between breast cancer and brain metastases diagnosis and KPS ≥ 90% independently predicted long survival. The appropriate short and long survival scores showed higher diagnostic accuracy for the prediction of short (AUC = 0.773) and long (AUC = 0.775) survival than the breast Graded Prognostic Assessment score (AUC = 0.498/0.615). A cumulative survival score (total score) showed significant association with overall survival (p = 0.001). Conclusion: We identified predictors independently impacting the prognosis after BCBM surgery. After external validation, the presented scores might become useful tools for the selection of proper candidates for BCBM surgery. Full article

(This article belongs to the Special Issue Brain Metastases in Breast Cancer)

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15 pages, 616 KiB

Open AccessArticle

Neratinib and Capecitabine for the Treatment of Leptomeningeal Metastases from HER2-Positive Breast Cancer: A Series in the Setting of a Compassionate Program

by Alessia Pellerino, Riccardo Soffietti, Francesco Bruno, Roberta Manna, Erminia Muscolino, Pierangela Botta, Rosa Palmiero and Roberta Rudà

Cancers 2022, 14(5), 1192; https://doi.org/10.3390/cancers14051192 - 25 Feb 2022

Cited by 12 | Viewed by 2270

Abstract

Background: Leptomeningeal metastasis is a neurological complication from HER2-positive breast cancer with a poor prognosis and limited treatment options. This study has evaluated the activity of neratinib in association with capecitabine in 10 patients with LM from HER2-positive BC after the failure of [...] Read more.

Background: Leptomeningeal metastasis is a neurological complication from HER2-positive breast cancer with a poor prognosis and limited treatment options. This study has evaluated the activity of neratinib in association with capecitabine in 10 patients with LM from HER2-positive BC after the failure of multiple lines of treatment, including trastuzumab-based therapy, within a compassionate program, and a comparison was made with a historical control group of 10 patients. Methods: Patients aged ≥ 18 years with histological diagnosis of primary HER2-positive BC, either amplified or mutated, and newly-diagnosed LM were enrolled. Coexistence of BM that has or has not received radiotherapy, as well as prior chemotherapy, hormone therapy, or monoclonal HER2-targeting antibodies or antibody–drug conjugates, were allowed, with the exclusion of lapatinib. Results: Six-months OS was 60% with a median OS of 10 months (95% CI: 2.00–17.0). Three-month intracranial PFS was 60% with a median intracranial PFS of 4.0 months (95% CI: 2.00–6.0). The neurological benefit was observed in 70% of patients with a median duration of neurological response of 6.5 months. The best radiological response was stable disease in 60% of patients. Conclusions: This small series shows that the combination of neratinib and capecitabine is a safe treatment in LM from heavily pretreated HER2-positive BC with clinical efficacy in some patients and is worth investigating in a larger study. Full article

(This article belongs to the Special Issue Brain Metastases in Breast Cancer)

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16 pages, 305 KiB

Open AccessArticle

The Usefulness of Prognostic Tools in Breast Cancer Patients with Brain Metastases

by Joanna Kufel-Grabowska, Anna Niwińska, Barbara S. Radecka, Shan Ali, Tomasz Mandat and Renata Duchnowska

Cancers 2022, 14(5), 1099; https://doi.org/10.3390/cancers14051099 - 22 Feb 2022

Cited by 2 | Viewed by 1913

Abstract

Background: Determining the proper therapy is challenging in breast cancer (BC) patients with brain metastases (BM) due to the variability of an individual’s prognosis and the variety of treatment options available. Several prognostic tools for BC patients with BM have been proposed. Our [...] Read more.

Background: Determining the proper therapy is challenging in breast cancer (BC) patients with brain metastases (BM) due to the variability of an individual’s prognosis and the variety of treatment options available. Several prognostic tools for BC patients with BM have been proposed. Our review summarizes the current knowledge on this topic. Methods: We searched PubMed for prognostic tools concerning BC patients with BM, published from January 1997 (since the Radiation Therapy Oncology Group developed) to December 2021. Our criteria were limited to adults with newly diagnosed BM regardless of the presence or absence of any leptomeningeal metastases. Results: 31 prognostic tools were selected: 13 analyzed mixed cohorts with some BC cases and 18 exclusively analyzed BC prognostic tools. The majority of prognostic tools in BC patients with BM included: the performance status, the age at BM diagnosis, the number of BM (rarely the volume), the primary tumor phenotype/genotype and the extracranial metastasis status as a result of systemic therapy. The prognostic tools differed in their specific cut-off values. Conclusion: Prognostic tools have variable precision in determining the survival of BC patients with BM. Advances in local and systemic treatment significantly affect survival, therefore, it is necessary to update the survival indices used depending on the type and period of treatment. Full article

(This article belongs to the Special Issue Brain Metastases in Breast Cancer)

15 pages, 3006 KiB

Open AccessArticle

Landscape of Epidermal Growth Factor Receptor Heterodimers in Brain Metastases

by Malcolm Lim, Tam H. Nguyen, Colleen Niland, Lynne E. Reid, Parmjit S. Jat, Jodi M. Saunus and Sunil R. Lakhani

Cancers 2022, 14(3), 533; https://doi.org/10.3390/cancers14030533 - 21 Jan 2022

Cited by 4 | Viewed by 2407

Abstract

HER2+ breast cancer patients have an elevated risk of developing brain metastases (BM), despite adjuvant HER2-targeted therapy. The mechanisms underpinning this reduced intracranial efficacy are unclear. We optimised the in situ proximity ligation assay (PLA) for detection of the high-affinity neuregulin-1 receptor, HER2-HER3 [...] Read more.

HER2+ breast cancer patients have an elevated risk of developing brain metastases (BM), despite adjuvant HER2-targeted therapy. The mechanisms underpinning this reduced intracranial efficacy are unclear. We optimised the in situ proximity ligation assay (PLA) for detection of the high-affinity neuregulin-1 receptor, HER2-HER3 (a key target of pertuzumab), in archival tissue samples and developed a pipeline for high throughput extraction of PLA data from fluorescent microscope image files. Applying this to a large BM sample cohort (n = 159) showed that BM from breast, ovarian, lung and kidney cancers have higher HER2-HER3 levels than other primary tumour types (melanoma, colorectal and prostate cancers). HER2 status, and tumour cell membrane expression of pHER2(Y^1221/1222) and pHER3(Y¹²²²) were positively, but not exclusively, associated with HER2-HER3 frequency. In an independent cohort (n = 78), BM had significantly higher HER2-HER3 levels than matching primary tumours (p = 0.0002). For patients who had two craniotomy procedures, HER2-HER3 dimer levels were lower in the consecutive lesion (n = 7; p = 0.006). We also investigated the effects of trastuzumab and pertuzumab on five different heterodimers in vitro: HER2-EGFR, HER2-HER4, HER2-HER3, HER3-HER4, HER3-EGFR. Treatment significantly altered the absolute frequencies of individual complexes in SKBr3 and/or MDA-MB-361 cells, but in the presence of neuregulin-1, the overall distribution was not markedly altered, with HER2-HER3 and HER2-HER4 remaining predominant. Together, these findings suggest that markers of HER2 and HER3 expression are not always indicative of dimerization, and that pertuzumab may be less effective at reducing HER2-HER3 dimerization in the context of excess neuregulin. Full article

(This article belongs to the Special Issue Brain Metastases in Breast Cancer)

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Review

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18 pages, 1452 KiB

Open AccessReview

Radiotherapy for Leptomeningeal Carcinomatosis in Breast Cancer Patients: A Narrative Review

by Ewa Pawłowska, Anna Romanowska and Jacek Jassem

Cancers 2022, 14(16), 3899; https://doi.org/10.3390/cancers14163899 - 12 Aug 2022

Cited by 3 | Viewed by 2119

Abstract

Leptomeningeal carcinomatosis (LC), defined as the infiltration of the leptomeninges by cancer cells, is a rare oncological event with the most common etiology being breast cancer (BC), lung cancer, and melanoma. Despite innovations in radiotherapy (RT), firm evidence of its impact on survival [...] Read more.

Leptomeningeal carcinomatosis (LC), defined as the infiltration of the leptomeninges by cancer cells, is a rare oncological event with the most common etiology being breast cancer (BC), lung cancer, and melanoma. Despite innovations in radiotherapy (RT), firm evidence of its impact on survival is lacking, and concerns are related to its possible neurotoxicity. Owing to a paucity of data, the optimal treatment strategy for LC remains unknown. This review discusses current approaches, indications, and contraindications for various forms of RT for LC in BC. A separate section is dedicated to new RT techniques, such as proton therapy. We also summarize ongoing clinical trials evaluating the role of RT in patients with LC. Full article

(This article belongs to the Special Issue Brain Metastases in Breast Cancer)

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15 pages, 2337 KiB

Open AccessReview

Actual, Personalized Approaches to Preserve Cognitive Functions in Brain Metastases Breast Cancer Patients

by Monika Konopka-Filippow, Dominika Hempel and Ewa Sierko

Cancers 2022, 14(13), 3119; https://doi.org/10.3390/cancers14133119 - 25 Jun 2022

Cited by 1 | Viewed by 1762

Abstract

Breast cancer (BC) is the most often diagnosed cancer among women worldwide and second most common cause of brain metastases (BMs) among solid malignancies being responsible for 10–16% of all BMs in oncological patients. Moreover, BMs are associated with worse prognosis than systemic [...] Read more.

Breast cancer (BC) is the most often diagnosed cancer among women worldwide and second most common cause of brain metastases (BMs) among solid malignancies being responsible for 10–16% of all BMs in oncological patients. Moreover, BMs are associated with worse prognosis than systemic metastases. The quality of life (QoL) among brain metastases breast cancer (BMBC) patients is significantly influenced by cognitive functions. Cancer-related cognitive deficits and the underlying neural deficits in BMBC patients can be caused via BMs per se, chemotherapy administration, brain irradiation, postmenopausal status, or comorbidities. Brain RT often leads to cognitive function impairment by damage of neural progenitor cells of the hippocampus and hence decreased QoL. Sparing the hippocampal region of the brain during RT provides protective covering of the centrally located hippocampi according to the patient’s clinical requirements. This article discusses the personalized strategies for treatment options to protect cognitive functions in BMBC patients, with special emphasis on the innovative techniques of radiation therapy. Full article

(This article belongs to the Special Issue Brain Metastases in Breast Cancer)

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16 pages, 2296 KiB

Open AccessReview

Salvage Treatment for Progressive Brain Metastases in Breast Cancer

by Mateusz Jacek Spałek and Tomasz Mandat

Cancers 2022, 14(4), 1096; https://doi.org/10.3390/cancers14041096 - 21 Feb 2022

Cited by 6 | Viewed by 2687

Abstract

Survival of patients with breast cancer has increased in recent years due to the improvement of systemic treatment options. Nevertheless, the occurrence of brain metastases is associated with a poor prognosis. Moreover, most drugs do not penetrate the central nervous system because of [...] Read more.

Survival of patients with breast cancer has increased in recent years due to the improvement of systemic treatment options. Nevertheless, the occurrence of brain metastases is associated with a poor prognosis. Moreover, most drugs do not penetrate the central nervous system because of the blood–brain barrier. Thus, confirmed intracranial progression after local therapy is especially challenging. The available methods of salvage treatment include surgery, stereotactic radiosurgery (SRS), fractionated stereotactic radiotherapy (FSRT), whole-brain radiotherapy, and systemic therapies. This narrative review discusses possible strategies of salvage treatment for progressive brain metastases in breast cancer. It covers possibilities of repeated local treatment using the same method as applied previously, other methods of local therapy, and options of salvage systemic treatment. Repeated local therapy may provide a significant benefit in intracranial progression-free survival and overall survival. However, it could lead to significant toxicity. Thus, the choice of optimal methods should be carefully discussed within the multidisciplinary tumor board. Full article

(This article belongs to the Special Issue Brain Metastases in Breast Cancer)

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16 pages, 324 KiB

Open AccessFeature PaperReview

Intracranial Response Rate in Patients with Breast Cancer Brain Metastases after Systemic Therapy

by Anna Niwinska, Katarzyna Pogoda, Agnieszka Jagiello-Gruszfeld and Renata Duchnowska

Cancers 2022, 14(4), 965; https://doi.org/10.3390/cancers14040965 - 15 Feb 2022

Cited by 3 | Viewed by 2435

Abstract

Brain metastases are detected in 5% of patients with breast cancer at diagnosis. The rate of brain metastases is higher in HER2-positive and triple-negative breast cancer patients (TNBC). In patients with metastatic breast cancer, the risk of brain metastases is much higher, with [...] Read more.

Brain metastases are detected in 5% of patients with breast cancer at diagnosis. The rate of brain metastases is higher in HER2-positive and triple-negative breast cancer patients (TNBC). In patients with metastatic breast cancer, the risk of brain metastases is much higher, with up to 50% of the patients having two aggressive biological breast cancer subtypes. The prognosis for such patients is poor. Until recently, little was known about the response to systemic therapy in brain metastases. The number of trials dedicated to breast cancer with brain metastases was scarce. Our review summarizes the current knowledge on this topic including very significant results of clinical trials which have been presented very recently. We focus on the intracranial response rate of modern drugs, including new antibody–drug conjugates, HER2- targeted tyrosine kinase inhibitors and other targeted therapies. We highlight the most effective and promising drugs. On the other hand, we also suggest that further efforts are needed to improve the prognosis, especially patients with TNBC and brain metastases. The information contained in this article can help oncologists make treatment-related decisions. Full article

(This article belongs to the Special Issue Brain Metastases in Breast Cancer)

9 pages, 856 KiB

Open AccessReview

Patient Eligibility and Results for Brain Metastasis in Phase 3 Trials of Advanced Breast Cancer: A Scoping Review

by Renata Duchnowska, Everardo D. Saad, Małgorzata Banaszek, Ewa Pawłowska, Hanna Liberek, Natalia Cichowska-Cwalińska and Jacek Jassem

Cancers 2021, 13(21), 5306; https://doi.org/10.3390/cancers13215306 - 22 Oct 2021

Viewed by 1541

Abstract

Background: Although brain metastases (BM) affect 5% of all breast cancer patients and 14% of those with metastatic disease, patients with BM are often excluded from participation in clinical trials. We conducted a structured assessment of the contemporary restrictions to enrolment of, and [...] Read more.

Background: Although brain metastases (BM) affect 5% of all breast cancer patients and 14% of those with metastatic disease, patients with BM are often excluded from participation in clinical trials. We conducted a structured assessment of the contemporary restrictions to enrolment of, and results for, patients with BM in phase 3 trials published over a period of 23 years in advanced breast cancer. Methods: We used PubMed to search for completed randomized trials published between 01/98 and 12/20. For all eligible trials, two authors independently abstracted data on general characteristics of the studies and detailed information on patient eligibility regarding the presence of BM. Results: We analyzed 210 trials, which enrolled 92,409 eligible patients. Of that total, 162 (77.1%) publications explicitly mentioned eligibility criteria related to the presence of BM and 75 (35.7%) trials reportedly allowed patients with BM, usually with restrictions related to prior brain treatment or stability of lesions. There was a significant increase over time in the percentages of trials allowing patients with BM (p < 0.001), and these trials were more frequently dedicated to HER2-positive or triple-negative disease (p = 0.001). Only 11 trials reported separate results for patients with BM at baseline. The direct treatment activity on BM was usually not reported, although in subgroup analyses the treatment effect in relative terms was usually better among patients with BM than in overall populations. Conclusion: Nearly 36% of phase 3 trials in advanced breast cancer over a 23-year period allowed patients with BM, and this practice is increasing over time. More research is needed to establish the activity of current and promising therapies in patients with BM. Full article

(This article belongs to the Special Issue Brain Metastases in Breast Cancer)

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