Metastatic bone disease from breast cancer: a review of minimally invasive techniques for diagnosis and treatment

Skeletal-related events in patients with metastatic bone disease include intractable severe pain, pathologic fracture, spinal cord and nerve compression, hypercalcemia and bone marrow aplasia. In patients with breast cancer, the skeleton is the most frequent site for metastases. Treatment options for metastatic bone disease in these patients include bisphosphonates, chemotherapeutic agents, opioids, hormonal therapy, minimally invasive/interventional and surgical techniques. Interventional oncology techniques for breast cancer patients with bone metastases include diagnostic (biopsy) and therapeutic (palliative and curative) approaches. In the latter, percutaneous ablation, augmentation and stabilization are included. The purpose of this article is to describe the basic concepts of biopsy, ablation, embolization and peripheral skeleton augmentation techniques in patients with metastatic bone disease from breast carcinoma. The necessity for a tailored approach applying different techniques for different cases and locations will be addressed.     

乳腺癌肝转移特征及诊疗

乳腺癌发病人数逐年攀升,相较于其他部位转移的患者,乳腺癌肝转移患者通常预后较差.目前国内外尚无针对乳腺癌肝转移诊疗的指南.本文旨在为乳腺癌肝转移的临床诊疗提供一定的思路和依据.本文对乳腺癌肝转移临床特点、发病机制的研究现状与治疗进展进行综述.早期肝转移患者往往没有明显症状或体征,考虑肝转移的患者最好行影像学引导下穿刺确...     

Metastasis to the breast--a clinical challenge in outpatient

Metastatic tumours of the breast are often misdiagnosed as a primary breast malignancy. This erroneous diagnosis can lead to unnecessary mutilating surgery and to delays in applying appropriate treatment. We have analyzed the clinical features of seven patients presenting initially with a breast mass which, after further investigation, proved to be metastasis from a non-breast primary tumour. The treatment of metastatic breast tumours depends on the nature of the primary tumour. Metastases of solid tumours are treated with local excision. Lymphomas are treated with appropriate systemic therapy. The prognosis for patients with metastatic tumours in the breast is poor.     

脊柱转移瘤脊髓压迫症的治疗进展

癌症患者脊柱转移是造成脊髓硬膜外压迫的重要病源。随着肿瘤治疗技术的改善,脊柱转移瘤患者生存期提高,转移性脊髓硬膜外压迫的发病率也随之增加。转移性硬膜外脊髓压迫当伴有脊柱不稳定时,可通过手术方式对脊髓周围进行减压,同时进行脊柱稳定性的重建。若肿瘤对放射线敏感而没有合并脊柱不稳定时,放疗是有效的治疗方式。目前,脊柱立体定向放疗、经皮微创技术如椎体成形术和后凸成形术、经皮椎弓根内固定术、射频消融术对于某些适合的脊柱转移瘤都已取的理想的治疗效果。     

Analysis of HER2 expression in primary urinary bladder carcinoma and corresponding metastases

OBJECTIVE: To evaluate the expression of HER2 receptors (previously reported to be over-expressed in malignant urothelium) in both primary tumours and metastases of transitional cell cancer, using two different staining methods and two different scoring techniques, considering the potential use of these receptors as targets for planned systemic anti-HER2 nuclide-based treatment. MATERIALS AND METHODS: HER2 expression was evaluated with two different immunohistochemical methods in 90 patients with primary urinary bladder cancer tumours and corresponding metastases. Sections were first stained with the commercially available breast cancer test kit (HercepTest, Dako, Glostrup, Denmark). Parallel sections were then stained with a modified HercepTest procedure. Two different evaluation criteria were compared; the HercepTest score that requires > or = 10% stained tumour cells (as for breast cancer) and a proposed 'Target score' that requires > 67% stained tumour cells. The latter score is assumed to be preferable for HER2-targeted radionuclide therapy. RESULTS: Using the HercepTest kit, the Target score gave lower fractions of positive primary tumours and metastases than the HercepTest score. The modified HercepTest staining procedure and Target score gave high HER2 values in 80% of primary tumours and 62% of metastases, which is considerably more than that obtained with the HercepTest staining and score. There was a significant decrease in HER2 positivity with increasing distance from the primary tumour. In nine sentinel-node metastases assessed, all but one were HER2-positive. Considering all regional metastases, 74% were positive, and of distant metastases, 47%; 72% of the patients with positive primary tumours also expressed HER2 in their metastases. CONCLUSIONS: When combining the modified HercepTest with customised evaluation criteria, more HER2-positive tumours were diagnosed. The degree of HER2 down-regulation was significantly higher in distant than in regional metastases. HER2-targeted therapy may be an alternative or complementary to other methods in the future treatment of metastatic urinary bladder carcinoma.     

Stereotactic radiotherapy in metastatic breast cancer

The treatment of metastatic breast cancer is largely focused on systemic therapy. However, over the past decades, there has been growing interest in the use of metastasis-directed therapy in selected cases presenting with an oligometastatic phenotype, i.e. low disease burden with a more indolent biology. Identification of the oligometastatic breast cancer population has, so far, proven elusive. Stereotactic radiotherapy offers an effective, non-invasive approach to ablate metastatic disease both in the brain and in extra-cranial settings. The advent of advanced imaging techniques for target definition, along with the ability to achieve highly conformal dose deposition with steep dose fall-off, enable safe implementation of extreme hypofractionated and single fraction regimens with ablative intent. There is growing evidence that radiation-based treatments are more cost-effective when compared to other ablative modalities. This article provides preliminary evidence that metastasis-direct ablation, with advanced radiotherapy techniques, may play an important role in the management of metastatic breast cancer patients, potentially improving clinical outcomes with minimal toxicity. However, prospective randomized controlled trials are needed to further the understanding of the interaction between systemic therapy and ablative irradiation. Additionally, research in genomic and molecular profiling is needed to characterize metastatic breast cancer patients who will most likely benefit from such combined treatment approaches.     

Centenarians and supercentenarians: a black swan. Emerging social,medical and surgical problems

Background

Five percent of all patients with breast cancer have distant metastatic disease at initial presentation. Because metastatic breast cancer is considered to be an incurable disease, it is generally treated with a palliative intent. Recent non-randomized studies have demonstrated that (complete) resection of the primary tumor is associated with a significant improvement of the survival of patients with primary metastatic breast cancer. However, other studies have suggested that the claimed survival benefit by surgery may be caused by selection bias. Therefore, a randomized controlled trial will be performed to assess whether breast surgery in patients with primary distant metastatic breast cancer will improve the prognosis.

Design

Randomization will take place after the diagnosis of primary distant metastatic breast cancer. Patients will either be randomized to up front surgery of the breast tumor followed by systemic therapy or to systemic therapy, followed by delayed local treatment of the breast tumor if clinically indicated. Patients with primary distant metastatic breast cancer, with no prior treatment of the breast cancer, who are 18 years or older and fit enough to undergo surgery and systemic therapy are eligible. Important exclusion criteria are: prior invasive breast cancer, surgical treatment or radiotherapy of this breast tumor before randomization, irresectable T4 tumor and synchronous bilateral breast cancer. The primary endpoint is 2-year survival. Quality of life and local tumor control are among the secondary endpoints. Based on the results of prior research it was calculated that 258 patients are needed in each treatment arm, assuming a power of 80%. Total accrual time is expected to take 60 months. An interim analysis will be performed to assess any clinically significant safety concerns and to determine whether there is evidence that up front surgery is clinically or statistically inferior to systemic therapy with respect to the primary endpoint.

Discussion

The SUBMIT study is a randomized controlled trial that will provide evidence on whether or not surgery of the primary tumor in breast cancer patients with metastatic disease at initial presentation results in an improved survival.

Trial registration

NCT01392586.     

Proven efficacy of zoledronic acid in the treatment of bone metastases in patients with breast cancer and other malignancies

Many advanced cancers, particularly breast cancer and prostate cancer, metastasize to the bone, resulting in painful lesions and skeletal complications. Intravenous bisphosphonate therapy is an important component of palliative care for patients with bone metastases, and pamidronate has been the standard of care for patients with breast cancer and multiple myeloma since 1996. However, zoledronic acid is the first bisphosphonate shown to significantly reduce skeletal morbidity in patients with a wide range of primary tumor types. Zoledronic acid has demonstrated efficacy in the management of hypercalcemia and metastatic bone disease. In phase III studies involving more than 3000 patients with multiple myeloma, breast cancer, prostate cancer, lung cancer, and other cancers, 4 mg zoledronic acid demonstrated consistent efficacy across a range of clinical end-points, and was safe and well tolerated when infused over 15 min. Based on these studies, zoledronic acid appears to be active in patients with bone metastases irrespective of tumor type, and should be considered as the standard of care for the treatment of bone metastases.     

Colorectal cancer: managing distant metastases

The best opportunity for cure in colorectal cancer is early diagnosis and complete excision of the primary disease. Currently, metastatic disease develops in about 50% of patients, most often in the liver. Resection of solitary liver metastases is warranted, and a 5-year survival of at least 25% can be expected. Patients with limited unilobar multiple metastases may also benefit from resection. Extensive metastatic disease to the liver may respond to single or combination chemotherapy. Response rates are highest with hepatic artery infusion chemotherapy, but improvement in survival has not clearly been shown. Solitary or limited lung metastases, when unassociated with other metastatic disease, should also be resected. Multiorgan involvement may respond to systemic chemotherapy but results are generally poor. Palliation is an important objective of therapy, involving not only anticancer treatment (surgery, chemotherapy, radiotherapy) but also general supportive care.     

Palliative systemic therapy and overall survival of 1,395 patients with advanced breast cancer – Results from the prospective German TMK cohort study

Data on treatment and outcome of advanced breast cancer in routine practice are rare, especially concerning recurrent disease, but important to complement the results from clinical trials and to improve the standard of care. We present data on choice of systemic first-line treatment, number of treatment lines, and survival of patients treated by medical oncologists in Germany.1395 patients recruited by 124 sites at start of first-line therapy into the ongoing, prospective German clinical cohort study TMK (Tumour Registry Breast Cancer) between February 2007 and October 2015 were analysed.The median OS was 33.8 months (95% CI 30.2–40.2) for HR-positive/HER2-negative, 38.2 months (95% CI 31.3–43.0) for HER2-positive and 16.8 months (95% CI 11.5–22.0) for triple negative breast cancer. Patients with triple negative tumours more often died before start of a third-line therapy than patients with HR-positive or HER2-positive tumours (44% vs. 25%). Use of taxane-based chemotherapies has increased since 2007, with 65% of all first-line chemotherapy-treatments containing taxanes in 2013–15 (60% HR-positive/HER2-negative, 75% HER2-positive, 56% triple negative). 52% of the patients with HR-positive/HER2-negative tumours received first-line endocrine therapy in 2013–15; when restricted to patients with only non-visceral metastases this percentage increased to 63%.To our knowledge, this is the first cohort study showing systemic first-line therapy for all subtypes of advanced breast cancer. Overall survival in the TMK is comparable to that reported by clinical trials despite the inclusion of older and comorbid patients.     

Esophagogastric Cancers Secondary to a Breast Primary Tumor Do Not Require Resection

Background Breast cancer metastasis to the gastrointestinal tract (GIT) is rare. When it does occur, the upper GIT is more frequently involved, and lobular infiltrating carcinoma apparently has a greater apparent predilection for the GIT than the ductal type does. This study reviewed the clinicopathological features of esophagogastric secondary tumors from breast cancer. Patients and Methods Patients with breast cancer metastases to the upper GIT referred to us for treatment of either esophageal or gastric cancers between November 1997 and November 2004 were identified from our database. The medical records of these patients were then reviewed for clinicopathological data and outcome. Results Nine patients with mean age of 71 (range: 57–90) years had median time of 6.5 (2.8–32.8) years between primary breast cancer diagnosis and upper GI metastasis. The sites of metastatic lesions included the lower esophagus (2 patients), gastroesophageal junction (1 patient), gastric body (3 patients), and pylorus (3 patients). Histological typing indicated 7 cases of the lobular form and 2 cases of ductal carcinoma. All but one biopsy specimen were estrogen receptor and CK7 positive. Treatment included hormonal therapy and stent in 3 patients, hormonal therapy alone in 1 patient, chemotherapy alone in 1 patient, chemotherapy and gastrojejunostomy in 1 patient, dilatation and stent in 1 patient, and palliative care only in 2 patients. The median survival following treatment of these metastases was 20 (range: 2.1–96.6) months. Conclusions The onset of nonspecific GIT symptoms in patients with a history of breast carcinoma should prompt the clinician to rule out the possibility of upper GIT metastasis even many years after the original breast cancer. The use of systemic therapy for breast cancer may result in longer survival.     

Current and future role of neoadjuvant therapy for breast cancer

Neoadjuvant systemic chemotherapy is a possible therapeutic approach for the treatment of locally advanced operable, primarily non-operable or inflammatory breast cancer. Neoadjuvant systemic chemotherapy is an option for breast cancer patients who would require adjuvant chemotherapy otherwise based on clinical and histological examination and imaging. The use of neoadjuvant systemic therapy in operable breast cancer is currently increasing because of its advantages that include higher rates of breast conserving surgery and the possibility of measuring early in-vivo response to systemic treatment. The timing of axillary sentinel lymph node diagnosis (i.e. before or after neoadjuvant chemotherapy) is critical in that it may influence the likelihood of axillary preservation. It is not yet clear if neoadjuvant therapy might improve outcomes in certain subgroups of breast cancer patients. Neoadjuvant treatment modalities require a close collaboration between oncology professionals, including surgeons, gynecologists, medical oncologists, radiation oncologists, radiologists and pathologists. The most important parameter for treatment success and improved overall survival is the achievement of a pathologic complete response (pCR), although the role of pCR in patients with luminal A like tumours might be less informative. Identification of patient subgroups with high pCR rates may allow less invasive surgical or radiological interventions. Patients not achieving a pCR may be candidates for postoperative clinical trials exploring novel systemic treatments.     

Factors influencing the time to development of brain metastases in breast cancer

This retrospective study analyzed risk factors influencing the time to development of brain metastases with the aim to facilitate the definition of a high-risk population among breast cancer patients. One hundred seventy-four breast cancer patients with brain metastases, treated with whole brain radiotherapy, were evaluated. Statistical analysis included hormone receptor status, HER2/neu status, tumour grading, tumour stage, young age at the time of diagnosis, adjuvant systemic treatment, palliative systemic treatment, metastatic sites (if brain metastases were not the first site of recurrence), and immunotherapy with trastuzumab. Time to development of brain metastases was significantly prolonged by systemic palliative treatment (p< or =0.0001) whereas high tumour grading (p< or =0.04) and trastuzumab therapy (p< or =0.04) significantly shortened this time span. Patients with the brain as first metastatic site, age>35 (p< or =0.001) and stage III (p< or =0.018) at the time of diagnosis had a significantly shorter time to development for brain lesions. These factors should be further validated by a prospective trial to identify a high-risk population amongst breast cancer patients and enable the development of screening programs for early detection.     

Combined multimodal treatment for liver and lung metastasis from colorectal cancer: a new therapeutic option?

The authors analyse which therapeutic strategy to adopt on the basis of prognostic factors and staging of hepatic and pulmonary metastases from colorectal cancer. They underline the effectiveness of combined multimodal therapy in the treatment of very advanced metastatic stages. 218 patients with metastases from colorectal cancer (12 pulmonary and 206 hepatic metastases) were treated from January 1980 to October 2000. Among these patients, 159 underwent surgery (4 pulmonary and 155 hepatic resections), 16 were reoperated on for metastatic relapse, 14 with multiple metastases underwent locoregional therapy and 29, deemed unresectable initially, were treated with neoadjuvant chemo- and radiotherapy. In the operated patient group the 5-year actuarial survival rate was 22% with an operative mortality of 3.8% and a morbidity of 17.5%. The 16 patients reoperated on for metastatic relapse had a 5-year actuarial survival of 21% with an operative mortality of 6.2% and a morbidity of 15.8%. The 14 patients treated with locoregional therapy had a median survival of 6 months whereas the 29 patients treated in two different periods with combined multimodal treatment had a response rate of 59.2%. Five patients had a complete response and 4 are currently disease-free. Surgical resection is at present the best known treatment for metastatic disease. In very advanced, as yet undisseminated stages, in which there is no surgical indication for metastases a neoadjuvant treatment is proposed if the primary tumour has already been completely resected. The aim of this therapeutic strategy, called combined multimodal therapy, is to obtain the disease regression with the aid of systemic chemo- and radiotherapy and to offer a chance of re-staging the disease.     

Intérêt de la documentation biologique de la maladie métastatique cérébrale dans le cancer du sein : à propos d’un cas

Breast cancer, after lung cancer, is the second major cause of brain metastases. In breast cancer, the prognosis is closely linked to the molecular subtype of the primary tumor. Targeted therapies, with or without cytotoxic treatment, have significantly modified overall survival in these patients. We report, the case of a patient suffering from breast cancer with brain metastasis in whom the biological documentation of the metastatic disease permitted to tailor the systemic treatment. Analysis of the surgical specimen revealed an immunohistochemical HER2 positive staining, which was not found in the primary tumor and therefore warranted trastuzumab administration. Another interesting insight based on this case report was to underline the phenotypic heterogeneity of the metastatic disease and its potential dynamic course as illustrated by the dissociated response to trastuzumab on body TEP-TDM in this particular patient. This case report also highlights the new place of the neurosurgeon in brain metastases management, not only as a participant in local treatment but also as a physician who is in fact involved in the delineation of the global oncological strategy in these patients as well as medical oncologists and radiation oncologists.     

Breast surgery in advanced breast cancer: local control in the presence of metastases

Recent reports have associated improved survival with surgical resection of primary breast cancer in patients presenting with synchronous metastases. These series can be criticized for selection bias as an explanation for improved outcome. Mutlivariate analysis attempting to address selection is still compatible with an associated benefit. Until a prospective randomized trial answers this question with solid evidence, what treatment gives the patient the benefit of the doubt? It would appear to favor resection of the primary in selected patients in whom the metastatic disease has a chance of control with systemic therapy. Once the barrier of surgery in the presence of metastases is breached, questions regarding more frequent application of surgery and ablative irradiation for metachronous metastasis in selected patients arise. The time has come to address this issue as well.     

CT staging for breast cancer patients with poor prognostic tumours

The aim of this study was to assess the value of computed tomography (CT) staging of the chest, abdomen and pelvis in patients with poor prognostic tumours and no symptoms of metastatic disease in those who have undergone primary surgical management for the treatment of breast cancer.Patients who had primary operable invasive breast cancer treated by surgery over a 2-year period were retrospectively identified. Pathological data from the surgical resection were used to calculate the Nottingham Prognostic Index. Patients with no symptoms of distant metastases who underwent CT staging of the chest, abdomen and pelvis as a result of being placed in the poor prognostic group were identified. The presence and sites of metastatic disease or any indeterminate finding were documented. Additional investigations generated as a result of the staging CT and the outcome were also recorded.Sixty-seven patients (80%) in the poor prognostic group underwent a staging CT. Forty-seven patients (70%) had no signs of metastatic disease on the staging CT. Two patients (3%) were diagnosed with metastatic disease, on the basis of the initial CT scan. Eighteen patients (27%) had an indeterminate finding requiring further investigation, generating 21 additional imaging tests – following this only one additional patient was diagnosed with metastatic disease. Seventeen patients with an initially indeterminate finding did not have metastatic disease, giving a false-positive rate of 25%. In total, three patients (4%) had a final diagnosis of metastatic disease.The routine use of CT staging in patients with no symptoms of distant metastases with primary operable breast cancer even when in a poor prognostic group is of limited value, with a low pick-up rate of metastatic disease and considerable risk of false-positive findings.     

Colorectal peritoneal metastases: pathogenesis,diagnosis and treatment options – an evidence‐based update

Peritoneal metastases confer the worst survival among all sites in patients with metastatic colorectal cancer. They develop largely through transcoelomic spread, with a sequence of events that allow cells to first detach from primary tumours, survive in the peritoneal environment, attach to the peritoneal surface of organs and migrate into the submesothelial space to create a microenvironment conducive to metastatic growth. Diagnostic challenges have previously hindered early identification of peritoneal metastases. While advances in diagnostic modalities have improved our ability to identify peritoneal metastases, lesions under 0.5 cm remain challenging to detect. The advent of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with colorectal peritoneal metastases a favourable long‐term survival. Recent trials, however, have cast doubts on the efficacy of HIPEC, with the recent PRODIGE 7 trial showing no benefit from oxaliplatin based HIPEC in addition to good quality cytoreductive surgery in resectable disease. While peritoneal recurrence can be reliably predicted from high‐risk features in primary tumours such as a perforated cancer, ovarian metastases or T4a cancers, the use of prophylactic second look surgery with HIPEC or adjuvant HIPEC failed to demonstrate any survival benefit in high‐risk cases in recent clinical trials, raising further questions about the efficacy of HIPEC. With high failure rates from systemic chemotherapy in unresectable disease, novel surgical techniques such as pressurized intraperitoneal aerolized chemotherapy are being investigated in clinical trials worldwide. Further collaborative research is needed to explore newer avenues of treatment for this poor prognostic cohort.     

The presentation of contralateral axillary lymph node metastases from breast carcinoma: a clinical management dilemma

Metastases to the contralateral axillary lymph nodes in breast cancer patients are uncommon. Involvement of the contralateral axilla is a manifestation of systemic disease (stage IV) or a regional metastasis from a new occult primary (T0N1, stage II). The uncertain laterality of the cancer responsible for these metastases complicates overall disease staging and is a management dilemma for clinicians. Seven women who developed contralateral axillary metastases (CAM), but did not have evidence of systemic disease were identified. Patient demographics, histopathologic tumor characteristics, treatment and outcome were examined. The median age was 49 years. A family history of breast cancer was present in six (86%). The initial breast cancers were located in all quadrants. They were generally hormone receptor negative, HER-2/neu overexpressing and associated with lymphovascular invasion. There was a median interval of 71 months between initial breast cancer diagnosis and CAM presentation. Surgical management of the CAM included simple excision in one (14%) and axillary lymph node dissection in five (71%). Adjuvant treatment consisted of chemotherapy in seven (100%) and hormonal therapy in one (14%). The median follow-up from the diagnosis of CAM was 35 months and three women were alive without disease, two were alive with disease and two had died of disease. With surgical treatment, there were no axillary recurrences in this series. When patients present with CAM and no evidence of systemic disease or a new primary in the contralateral breast, surgical treatment should be considered for local control and possibly improved relapse-free survival.