Metastatic disease of the breast and local recurrence

Multimodality primary therapies for breast cancer combined with earlier detection have led to a sharp decline in the death rate from breast cancer in the UK over the last 40 years in the face of a rising incidence. The latest UK statistics from Cancer Research UK report 50,285 new cases of breast cancer in 2011 with 11,716 deaths from breast cancer recorded in 2012. Crudely, this equates to a cure rate in excess of 75% for all comers. Despite this good news, there are still significant numbers of women (and men) who suffer from either a local recurrence or metastatic disease following apparently successful treatment for early breast cancer (Stage I–III). Only a minority of individuals, 6.6% with the stage recorded at diagnosis, present with stage IV disease. This review considers the treatment options available to individuals with locally recurrent and advanced breast cancer (ABC).     

Metastatic disease of the breast and local recurrence

Multimodality primary therapies for breast cancer combined with earlier detection have led to a sharp decline in the death rate from breast cancer in the UK over the last 40 years in the face of a rising incidence. The latest UK statistics from Cancer Research UK report 55,122 new cases of breast cancer in 2015 with 11,563 deaths from breast cancer recorded in 2016. Crudely, this equates to a cure rate of around 80% for all comers and demonstrates a clear improvement in outcome with 50,285 new cases in 2011 and 11,716 deaths in 2012. Despite this good news, there are still significant numbers of women (and men) who suffer from either a local recurrence or metastatic disease following apparently successful treatment for early breast cancer (Stage I to III). Only a minority of individuals, 6.6% with the stage recorded at diagnosis, present with stage IV disease. This review considers the treatment options available to individuals with locally recurrent and advanced breast cancer (ABC).     

Metastatic disease of the breast and local recurrence of breast cancer

Breast cancer is a major health problem worldwide with over 1 million new cases diagnosed each year. The aim of treatment is to achieve good loco-regional control, provide appropriate adjuvant therapy and treat potential micro-metastasis. Early detection with breast screening and better treatment options have improved outcome. However approximately 40% of patients will suffer a recurrence and still 35–40% will eventually present with metastatic disease. Metastatic disease is incurable with the median survival being 2–3 years. Several therapies have been shown to maintain a good quality of life whilst prolonging survival. In certain sub-groups of breast cancer, that is, human epidermal growth factor receptor 2 (HER2)-positive cancer the advent of trastuzumab has improved survival rates. A multidisciplinary team approach is essential to obtain the diagnosis and plan the appropriate treatment. The diagnosis of metastatic disease brings distress to patients and their relatives and support should be available from palliative care teams.     

Metastatic disease of the breast and local recurrence of breast cancer

Breast cancer is a major health problem worldwide with over one million new cases diagnosed each year. The aim of treatment is to achieve good loco-regional control, provide appropriate adjuvant therapy and treat potential micro-metastasis. Good loco-regional control is essential to minimize local recurrence rates with histological clear margin being the most important factor. Several prognostic factors can be used to guide suitable adjuvant therapy. The most important is hormone sensitivity and the use of hormone manipulation has improved both recurrence rates and overall survival. Early detection with breast screening and better treatment options have improved outcome, but still 35–40% of patients will eventually present with metastatic disease. Metastatic disease is incurable, but several therapies have been shown to maintain a good quality of life whilst prolonging survival. A multidisciplinary team approach is essential to obtain the diagnosis and plan the appropriate treatment. The diagnosis of metastatic disease brings distress to patients and their relatives and support should be available from palliative care teams.     

Survival Impact of Integrative Cancer Care in Advanced Metastatic Breast Cancer

Abstract: Integrative cancer treatment is of substantial interest to many cancer patients. Research is needed to evaluate the effects of integrative treatment on patient outcomes. We report survival data for a consecutive case series of advanced metastatic breast cancer patients who received a comprehensive clinical program combining conventional treatments with nutrition and supplementation, fitness and mind‐spirit instruction at the Block Center for Integrative Cancer Treatment. Treatment outcomes using integrative care for this disease have not previously been documented; survival data will thus contribute to decisions concerning future research directions and design. Ninety consecutive patients with metastatic breast cancer diagnosed during 1984–1997 who received chemotherapy at the integrative cancer center were included. Prognostic factors, treatments and survival from onset of metastases were determined from analysis of scans, labs, pathology and medical records. The log‐rank test and Cox proportional hazards analyses were used, and a Kaplan–Meier curve was calculated. All patients had metastatic disease at baseline, 96% were relapsed and 52% had received prior chemotherapy for metastatic disease. Median age at onset of metastasis was 46 years. Median survival was 38 months (95% CI 27,48). Published literature on populations with somewhat more favorable prognostic factors treated in conventional clinics showed median survivals of 20 to 23 months. Through the 1990s, median survival reported in metastatic breast cancer trials or observations generally ranged from 12 to 24 months. Five‐year survival was 27% for Center versus 17% for comparison patients. Despite a higher proportion of younger and relapsed patients, survival of metastatic breast cancer patients at the Center was approximately double that of comparison populations and possibly even higher compared to trials published during this period. Explanations for the advantage relative to conventional treatment alone may include the nutritional, nutraceutical, exercise and psychosocial interventions, individually or in combination; self‐selection of patients cannot be ruled out. Further research to evaluate the impact of integrative breast cancer treatment on survival is warranted.     

The presentation,management and outcome of inflammatory breast cancer cases in the UK: Data from a multi-centre retrospective review

ObjectivesInflammatory Breast cancer (IBC) is a rare but aggressive form of breast cancer. Its incidence and behaviour in the UK is poorly characterised. We collected retrospective data from hospitals in the UK and Ireland to describe the presentation, pathology, treatment and clinical course of IBC in the UK.Materials and methodsPatients with IBC diagnosed between 1997–2014 at fourteen UK and Irish hospitals were identified from local breast unit databases. Patient characteristics, tumour pathology and stage, and details of surgical, systemic and radiotherapy treatment and follow-up data were collected from electronic patient records and medical notes.ResultThis retrospective review identified 445 patients with IBC accounting for 0.4–1.8% of invasive breast cancer cases. Median follow-up was 4.2 years. 53.2% of tumours were grade 3, 56.2% were oestrogen receptor positive, 31.3% were HER2 positive and 25.1% were triple negative. 20.7% of patients had distant metastases at presentation. Despite trimodality treatment in 86.4%, 40.1% of stage III patients developed distant metastases. Five-year overall survival (OS) was 61.0% for stage III and 21.4% for stage IV patients.ConclusionsThis is the largest series of UK IBC patients reported to date. It indicates a lower incidence than in American series, but confirms that IBC has a high risk of recurrence with poor survival despite contemporary multi-modality therapy. A national strategy is required to facilitate translational research into this aggressive disease.     

Prolonged trastuzumab therapy in a patient with recurrent breast cancer and anthracycline-induced cardiac failure

Current practice precludes patients with pre-existing cardiac dysfunction from trastuzumab therapy. A 57-year-old patient with HER2 positive metastatic breast cancer and anthracycline-induced cardiac failure was safely treated with trastuzumab. At 46 months, left ventricular ejection fraction (LVEF) did fall to 38.3%, but 8 months later has recovered to 47%. She remains disease free and asymptomatic from cardiac dysfunction more than 6 years following breast cancer recurrence. We review the evidence for the use of trastuzumab in patients with controlled cardiac dysfunction, and suggest this group of patients should be considered for treatment with trastuzumab if no other or only less efficacious therapeutic options are available.     

Surgical considerations for patients with metastatic renal cell carcinoma

Among patients with renal cell carcinoma (RCC), 25–30% present with metastatic disease at the time of initial diagnosis. Despite the ever-increasing array of treatment options available for these patients, surgery remains one of the cornerstones of therapy. Proper patient selection for cytoreductive surgery is paramount to its effective use in the management of patients with metastatic RCC despite the decrease in reported morbidity rates. We explore the evolving role cytoreductive surgery in metastatic RCC spanning the immunotherapy era to the targeted therapy era. Despite significant advances in the management of patients with metastatic RCC, further evidence on the definitive role of cytoreductive surgery in the targeted therapy era is awaited through large randomized trials.     

Clinical outcomes of cyclin-dependent kinase 4–6 (CDK 4–6) inhibitors in patients with male breast cancer: A multicenter study

BackgroundSince breast cancer is less common in men than in women, data on the use of new therapeutic agents, including cyclin-dependent kinase 4–6 (CDK 4–6) inhibitors, are limited in patients with metastatic hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) male breast cancer. Therefore; we aimed to investigate the treatment responses of metastatic HR+, HER2-male breast cancer patients treated with CDK 4–6 inhibitors in a multicenter real-life cohort.MethodsMale patients with a diagnosis of HR+ and HER2-metastatic breast cancer, treated with any CDK 4–6 inhibitor, were included in the study. Demographic and clinical characteristics of the patients were recorded. We aimed to determine progression-free survival (PFS) time, response rates and drug related side effects.ResultsA total 25 patients from 14 institutions were recruited. The mean age at diagnosis was 57 years. Median follow-up was 19.53 (95% CI: 14.04–25.02) months. The overall response rate was 60%. While the median PFS was 20.6 months in the whole cohort, it wasn't reached in those using CDK 4–6 inhibitors in first line and 10 months in the subsequent lines (p:0.009). No new adverse events were encountered.ConclusionIn our study, we found that CDK 4–6 inhibitors are effective and safe options in men with HR+ and HER2-metastatic breast cancer as in women. Our results support the use of CDK 4–6 inhibitor-based combinations in the first-line treatment of HR+ and HER2-metastatic male breast cancer.     

Incidence of isolated local breast cancer recurrence and contralateral breast cancer: A systematic review

An increasing number of women is surviving breast cancer and due to that at risk of developing an isolated ipsilateral breast tumor recurrence (IBTR) or a contralateral breast cancer (CBC). Patients' main concern is cancer recurrence. Patient counseling on breast cancer recurrence is challenging. In order to provide healthcare professionals and patients more guidance, a systematic literature review of the incidence of isolated IBTR and CBC in women diagnosed with early invasive breast cancer was performed. Medline, EMBASE and the Cochrane Library were searched from 2000 until October 2015. Multicenter studies reporting an IBTR or CBC rate in curatively treated adult females diagnosed with invasive breast cancer were included. The initial search yielded 6998 potentially relevant articles. Twenty were eligible for inclusion, representing 25 recurrence incidence rates. Both isolated IBTR and CBC incidence rates steadily increased with the length of follow-up, indicating that IBTR and CBC occur even more than 15 years after diagnosis. The annual incidence rate of isolated IBTR and CBC in women diagnosed with an early invasive breast cancer was 0.6% (range: 0.4–1.1%) and 0.5% (range: 0.2–0.7%), respectively. Analyzed data were lacking information about important risk factors and given treatment with regard to the incidence of recurrence, which hampers the prediction of patient tailored recurrence risks. The presented rates are therefore the best available estimates of isolated IBTR and CBC annual incidence rates based on the current literature. Healthcare professionals could use these rates in their communication with patients diagnosed with early invasive breast cancer.     

Implications of Anthracycline‐Resistant and Taxane‐Resistant Metastatic Breast Cancer and New Therapeutic Options

Abstract: Patients with advanced or metastatic breast cancer commonly develop disease resistant to chemotherapy (typically anthracyclines and taxanes), which presents a major obstacle to therapy and leaves few effective treatment options. Drug resistance can occur due to various mechanisms including modification of drug efflux membrane transporters such as P‐glycoprotein, as well as alterations in β‐tubulin. The novel epothilone B analog, ixabepilone, which has low susceptibility to various drug‐resistance mechanisms, has demonstrated preclinical activity in drug‐resistant breast cancer. The clinical activity of ixabepilone was evaluated in metastatic breast cancer patients with highly pretreated and/or resistant/refractory disease. Results were reviewed from three phase II trials in which ixabepilone was administered as monotherapy and one phase III trial that evaluated ixabepilone in combination with capecitabine. As a single agent, ixabepilone demonstrated activity in women who were heavily pretreated and resistant to an anthracycline, a taxane, and/or capecitabine. The combination of ixabepilone and capecitabine was significantly more active than capecitabine alone in patients with prior treatment or resistance to anthracyclines and taxanes. Treatment‐related adverse events were generally low grade except for grade 3/4 toxicities, including neutropenia (53–54%) and reversible peripheral sensory neuropathy (14–16%). Ixabepilone has significant activity in patients with heavily pretreated metastatic breast cancer who are disease resistant or refractory to anthracyclines and taxanes. Further clinical evaluation of this agent in patients with drug‐resistant breast cancer and in specific patient subsets is warranted.     

Major Changes in Chemotherapy Regimens Administered to Breast Cancer Patients During 2000–2008 in the Netherlands

There is little information available on the patterns of chemotherapy regimens administered in daily practice to patients with early stage and metastatic or recurrent breast cancer. To determine the trends in type of chemotherapy regimens used in breast cancer patients, newly diagnosed breast cancer patients in the period 2000–2008 who received chemotherapy were identified from the Eindhoven Cancer Registry (ECR) and linked to the PHARMO RLS, including data on, e.g., in‐ and outpatient drug use. Chemotherapy regimens were classified based on the received combinations and sequences. Trends in the distribution of adjuvant chemotherapy regimens (for early‐stage breast cancer) and palliative chemotherapy regimens (for metastatic or recurrent breast cancer) were determined and stratified by Her2/neu status when possible. In this study, 422 patients diagnosed with early‐stage breast cancer received adjuvant chemotherapy. The use of CMF (cyclophosphamide, methotrexate, and 5‐fluorouracil) decreased from 90% in 2000 to almost none since 2005. Administration of regimens that included anthracyclines increased from 4% in 2000 to 96% in 2005, but decreased to 68% in 2008. The use of trastuzumab‐ and taxane‐containing regimens (with or without anthracyclines) increased from 2005 onwards to 24% and 34%, respectively, in 2008. Among the 82 breast cancer patients who received palliative chemotherapy at diagnosis or after breast cancer recurrence, the use of CMF and anthracyclines (without taxanes) decreased, while the use of taxanes (with or without anthracyclines) increased (26% in 2008). Trastuzumab was used as palliative chemotherapy from 2003 onwards, with 22% of the metastatic breast cancer patients receiving trastuzumab‐containing regimens in 2008, and bevacizumab was administered since 2007 with 19% of the patients receiving bevacizumab‐containing regimens in 2008. In conclusion, major changes have taken place in the chemotherapeutic treatment of patients with early and recurrent breast cancer. These changes reflect the key findings from large clinical trials, as incorporated in the Dutch guidelines.     

Treatment of cancer of the liver. Twenty years'' experience with infusion and resection in 414 patients.

The factors influencing survival for patients with cancer of the liver were studied by reviewing the records of 414 patients operated on in a private oncology practice. Approximately half (47%) had colorectal metastasis; 17% had metastatic breast carcinoma, 14% had malignant hepatoma, 5% had metastatic melanoma, and the remainder had a variety of primary cancers. Eighty-two per cent of all patients had advanced liver disease when first diagnosed. One quarter of the patients had some type of resection; the remainder had abdominal exploration plus insertion of an infusion catheter into the hepatic artery. The postoperative mortality rate after liver resection for 108 patients was 6.5%. After resection, the most important prognostic factor influencing survival was the presence or absence of extrahepatic metastases. When possible, resection was by far the best treatment available, and the best results were seen in patients who had resection of a solitary lesion. For advanced disease, when resection was not possible, intra-arterial chemotherapy, primarily with 5-fluorouracil (5-FU), was associated with response rates of 36% for colorectal cancer, 45% for breast cancer, 13% for hepatocellular cancer, 12% for melanoma, and 14% for metastases from other primary sites. The patients who responded to infusion lived longer than those who did not respond. For example, at 18 months, 26% of the responders with colorectal cancer were alive, as were 50% of the responders with breast cancer and 40% of the responders with hepatocellular cancer. In contrast, at 18 months, there were no survivors among the nonresponders with colorectal, breast, or hepatocellular cancer. For those patients treated solely by infusion chemotherapy, the extent of disease in the liver was the most reliable factor in predicting the length of survival. However, very few patients treated in this manner lived longer than 3 years.     

Pancreatic cancer

Pancreatic cancer accounts for 3% of all cancers in the UK; 7000 new cases are diagnosed annually and a similar number die from the disease each year. It has an insidious onset and, as a result, presentation is usually late, with only about 10–20% of patients having disease amenable to surgical resection. Following resection, the median survival is 11–20 months and the 5-year survival is 7–25%. Patients with unresectable locally advanced disease have a median survival of 6–11 months, and those with metastatic disease have a median survival of 2–6 months. Accurate staging has a vital role in the management of pancreatic tumours now that non-surgical palliative options are available. Computed tomography is currently the imaging modality of choice for diagnosis and staging of pancreatic cancer. With recent advances in magnetic resonance imaging and endoscopic ultrasonography, it is now possible to improve the accuracy of preoperative staging, particularly with respect to local invasion and regional node involvement. Resection is the only treatment that offers the potential of cure; ideally, an R0 resection should be aimed for. Chemotherapy renders a survival advantage in the adjuvant setting, even in patients undergoing R1 resections. Palliative chemotherapy can improve survival by 10–15% and other palliative therapies are aimed at relieving jaundice, controlling pain, treating malabsorption and reversing cancer cachexia.     

Estimation of an evidence-based benchmark for the optimal endocrine therapy utilization rate in breast cancer

BackgroundThere are no evidence-based benchmarks to establish optimal rates of use of endocrine therapy in the whole breast cancer population. Reported utilization rates vary widely. The aim of the study was to estimate the optimal proportion of breast cancer patients who should receive endocrine therapy based on treatment guideline recommendations and to compare this with actual treatment rates.MethodsAn optimal endocrine therapy utilization tree was constructed based on indications from evidence-based treatment guidelines. Frequency data on patient and tumour attributes were obtained from Australian cancer registries where possible and merged with the guideline recommendations to calculate the optimal utilization rate. These were compared with actual proportions obtained from published reports.ResultsAccording to the best available evidence, the proportion of invasive breast cancer patients in whom endocrine therapy is indicated at diagnosis is 67%. Endocrine therapy is under-utilized in Australia (actual utilization rate 41%), and USA (35%), but approximate the benchmark rate in the UK (75%) and Italy (63%).ConclusionThis evidence-based model provides a benchmark for optimal endocrine therapy utilization rates in the breast cancer population, and comparison of best practice evidence and actual treatment. The results show an underutilization of endocrine therapy in Australia and the USA, with more appropriate utilization in the UK and Italy.     

Epidemiology,Aetiology, and Pathogenesis of Renal Cell Carcinoma

Significant advances in molecular medicine have made renal cell carcinoma (RCC) the prototype solid organ malignancy for targeted medical cancer treatment. Theseis new options have made it possible to prolong the life of patients with metastatic disease. However, we are far away from thoroughly understanding the molecular processes of RCC development let alone from being able to cure advanced renal cancer. RCC is the most common renal neoplasia and it remains a very aggressive and often fatal disease.There are several known histologic subtypes of this heterogeneous tumor entity with associated distinct molecular alterations and different clinical outcomes [1], [2], [3], [4]. The clear cell renal cell carcinoma (ccRCC) is the most common and apparently most aggressive RCC subtype with the highest rates of local invasion, metastasis and mortality. It constitutes 70–80% of all renal cancers [1], [5]. It is estimated that more than 30% of patients with RCC have metastatic disease at the time of diagnosis and 30% of organ-confined RCCs will develop metastatic disease after local treatment [6]. Thus, RCC remains a very major challenge.     

Improved survival in metastatic breast cancer 1985–2016

PurposeIn the last 25 years new treatment options in breast cancer have evolved. We wanted to determine whether the survival of; patients with metastatic breast cancer have improved during this period.MethodsPatients consecutively diagnosed with disseminated breast cancer 1985–2014 in the County of Kalmar, Sweden, were identified and followed to 2016. Survival was calculated for each successive 5 year interval. Separate analyses were performed for pts with ER and/or PR and HER2 positive tumours resp.ResultsMedian survival of the 784 patients increased successively from 13 to 33 months. Five year survival increased from 10 to 27%. Patients with high grade primary tumours had the shortest post recurrence survival time but their median survival increased significantly by time from 12 to 30 months, 3 year survival from 16 to 38% and 5 year from 5 to 20%. Median survival for patients with grade 2 tumours was 2 years and did not improve. Only 47 patients had grade 1 tumours and their median survival of 4 years did not change.Median survival for HER2 positive patients treated before the introduction of trastuzumab in year 2000 was 14 months and after 2000 29 months, 5 year survival improved from 2 to 31%.ConclusionsSurvival in metastatic breast cancer improved 1985–2016. For the first time a significant increase in survival time for patients with metastasis from fast-growing grade 3 tumours was seen. The most striking improvement was achieved in the HER2 positive subset.     

Renal cancer

Renal carcinoma is a reasonably common cancer in the UK. Fortunately, its diagnosis is nowadays much earlier due to the increased utilization of radiological imaging. While surveillance is an option, particularly in older/comorbid patients, nephron-sparing surgery remains the gold standard treatment for small renal masses. Laparoscopic, robotic or open partial nephrectomy have excellent cure rates. For larger tumours, radical nephrectomy may be required. This again can be performed laparoscopically, robotically or in an open manner. The classic presentation of renal mass, haematuria and loin pain is a late presentation – many of these patients will already have metastatic disease. Although non-curable, treatments are available for metastatic disease. Surgical options in the form of cytoreductive nephrectomy and metastasectomy can improve overall survival. Tyrosine kinase inhibitors, other targeted agents and immune check point inhibitors constitute the non-surgical treatments and have demonstrated increases in survival.     

Pancreatic cancer

Pancreatic cancer accounts for 3% of all cancers in the UK; 7000 new cases are diagnosed annually and a similar number die from the disease each year. It has an insidious onset and as a result presentation is usually late, with only about 10–20% of patients having disease amenable to surgical resection. Following resection, the median survival is 11–20 months and the 5-year survival is 7–25%. Patients with unresectable locally advanced disease have a median survival of 6–11 months, and those with metastatic disease have a median survival of 2–6 months. Accurate staging has a vital role in the management of pancreatic tumours now that non-surgical palliative options are available. Computed tomography is the imaging modality of choice for diagnosis and staging of pancreatic cancer. With recent advances in magnetic resonance imaging and endoscopic ultrasonography, it is now possible to improve the accuracy of preoperative staging, particularly with respect to local invasion and regional node involvement. Resection is the only treatment that offers the potential of cure; ideally, an R0 resection should be aimed for. Chemotherapy renders a survival advantage in the adjuvant setting, even in patients undergoing R1 resections. Palliative chemotherapy with gemcitabine can improve survival by 10–15% and other palliative therapies are aimed at relieving jaundice, controlling pain, treating malabsorption and reversing cancer cachexia.     

Renal cancer

Renal carcinoma is a reasonably common cancer in the UK. Fortunately, its diagnosis is nowadays much earlier due to the increased utilization of radiological imaging. Whilst surveillance is an option, particularly in older/comorbid patients, nephron sparing surgery remains the gold standard treatment for small renal masses. Laparoscopic, robotic or open partial nephrectomy have excellent cure rates. For larger tumours, radical nephrectomy may be required. This again can be performed laparoscopically, robotically or in an open manner. The classic presentation of renal mass, haematuria and loin pain is a late presentation – many of these patients will already have metastatic disease. Although non-curable, treatments are available for metastatic disease. Surgical options in the form of cytoreductive nephrectomy and metastasectomy can improve overall survival. Tyrosine kinase inhibitors and other targeted novel agents contribute the non-surgical treatments and have demonstrated increases in survival.