Expert UK consensus on the definition of high risk of recurrence in HER2-negative early breast cancer: A modified Delphi panel.

BACKGROUND: There is currently no standardised definition for patients at high risk of recurrence of human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC; stages 1-3) after surgery. This modified Delphi panel aimed to establish expert UK consensus on this definition, separately considering hormone receptor (HR)-positive and triple-negative (TN) patients. METHODS: Over three consecutive rounds, results were collected from 29, 24 and 22 UK senior breast cancer oncologists and surgeons, respectively. The first round aimed to determine key risk factors in each patient subgroup; subsequent rounds aimed to establish appropriate risk thresholds. Consensus was pre-defined as ≥70% of respondents. RESULTS: Expert consensus was achieved on need to assess age, tumour size, tumour grade, number of positive lymph nodes, inflammatory breast cancer and risk prediction tools in all HER2-negative patients. There was additional agreement on use of tumour profiling tests and biomarkers in HR-positive patients, and pathologic complete response (pCR) status in TN patients. Thresholds for high recurrence risk were subsequently agreed. In HR-positive patients, these included age <35 years, tumour size >5 cm (as independent risk factors); tumour grade 3 (independently and combined with other high-risk factors); number of positive nodes ≥4 (independently) and ≥1 (combined). For TN patients, the following thresholds reached consensus, both independently and in combination with other factors: tumour size >2 cm, tumour grade 3, number of positive nodes ≥1. CONCLUSIONS: The results may be a valuable reference point to guide recurrence risk assessment and decision-making after surgery in the HER2-negative eBC population.

A Multicentre Retrospective Study of Fulvestrant Use and Efficacy in Advanced/Metastatic Breast Cancer.

AIMS: Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. MATERIALS AND METHODS: Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. RESULTS: Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21-95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0-1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0-5) prior lines of endocrine therapy and median 0 (range 0-6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1-88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0-88). CONCLUSIONS: This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.

A survey to determine usual care after cancer treatment within the United Kingdom national health service.

BACKGROUND: Approximately one third of cancer survivors in the United Kingdom face ongoing and debilitating psychological and physical symptoms related to poor quality of life. Very little is known about current post-cancer treatment services. METHODS: Oncology healthcare professionals (HCPs) were invited to take part in a survey, which gathered both quantitative and free text data about the content and delivery of cancer aftercare and patient needs. Analysis involved descriptive statistics and content analysis. RESULTS: There were 163 complete responses from 278 survey participants; 70% of NHS acute trusts provided data. HCPs views on patient post-cancer treatment needs were most frequently: fear of recurrence (95%), fatigue (94%), changes in physical capabilities (89%), anxiety (89%) and depression (88%). A median number of 2 aftercare sessions were provided (interquartile range: 1,4) lasting between 30 and 60 min. Usually these were provided face-to-face and intermittently by a HCP. However, sessions did not necessarily address the issues HCPs asserted as important. Themes from free-text responses highlighted inconsistencies in care, uncertain funding for services and omission of some evidence based approaches. CONCLUSION: Provision of post-cancer treatment follow-up care is neither universal nor consistent in the NHS, nor does it address needs HCPs identified as most important.

Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study.

BACKGROUND: Approximately 40% of hormone receptor-positive, HER2-negative breast cancers (BCs) are associated with activating mutations of the phosphatidylinositol 3-kinase (PI3K) pathway. Pictilisib, a potent and highly specific class I pan-PI3K inhibitor, demonstrated preclinical activity in BC cell lines and may potentiate the effect of taxanes, benefiting patients with or without aberrant activation of the PI3K pathway. PEGGY (NCT01740336), a randomised, placebo-controlled phase II trial, examined whether pictilisib augments the anti-tumour activity of paclitaxel in patients with hormone receptor-positive, HER2-negative locally recurrent or metastatic BC (mBC). We report results from the protocol-specified interim analysis. PATIENTS AND METHODS: One hundred and eighty-three eligible patients were randomised (1:1) to receive paclitaxel (90 mg/m2 weekly for 3 weeks in every 28-day cycle) with either 260 mg pictilisib or placebo (daily on days 1-5 every week). The primary end point was progression-free survival (PFS) in the intention-to-treat (ITT) population and patients with PIK3CA-mutated tumours. Secondary end points included overall response rate (ORR), duration of response, and safety. RESULTS: In the ITT population, the median PFS was 8.2 months with pictilisib (n = 91) versus 7.8 months with placebo (n = 92) [hazard ratio (HR) for progression or death, 0.95; 95% confidence interval (CI) 0.62-1.46; P = 0.83]. In patients with PIK3CA-mutated tumours, the median PFS was 7.3 months for pictilisib (n = 32) versus 5.8 months with placebo (n = 30) (HR, 1.06; 95% CI 0.52-2.12; P = 0.88). ORR was similar between treatment arms. The safety profile of pictilisib was consistent with previous reports, with no new safety signals. Proportions of patients with grade ≥3 adverse events (AEs), serious AEs, and dose reductions/discontinuations due to AEs were higher with pictilisib. CONCLUSIONS: PEGGY did not meet its primary end point, revealing no significant benefit from adding pictilisib to paclitaxel for patients with hormone receptor-positive, HER2-negative locally recurrent or mBC. CLINICAL TRIAL NUMBER: NCT01740336.

Extreme chromosomal instability forecasts improved outcome in ER-negative breast cancer: a prospective validation cohort study from the TACT trial.

BACKGROUND: Chromosomal instability (CIN) has been shown to be associated with drug resistance and poor clinical outcome in several cancer types. However, in oestrogen receptor (ER)-negative breast cancer we have previously demonstrated that extreme CIN is associated with improved clinical outcome, consistent with a negative impact of CIN on tumour fitness and growth. The aim of this current study was to validate this finding using previously defined CIN thresholds in a much larger prospective cohort from a randomised, controlled, clinical trial. PATIENTS AND METHODS: As a surrogate measurement of CIN, dual centromeric fluorescence in situ hybridisation was performed for both chromosomes 2 and 15 on 1173 tumours from the breast cancer TACT trial (CRUK01/001). Each tumour was scored manually and the mean percentage of cells deviating from the modal centromere number was used to define four CIN groups (MCD1-4), where tumours in the MCD4 group were defined as having extreme CIN. RESULTS: In a multivariate analysis of disease-free survival, with a median follow-up of 91 months, increasing CIN was associated with improved outcome in patients with ER-negative cancer (P trend = 0.03). A similar pattern was seen in ER-negative/HER2-negative cancers (Ptrend = 0.007). CONCLUSIONS: This prospective validation cohort study further substantiated the association between extreme CIN and improved outcome in ER-negative breast cancers. Identifying such patients with extreme CIN may help distinguish good from poor prognostic groups, and therefore support treatment and risk stratification in this aggressive breast cancer subtype.

Germline CDH1 mutations in bilateral lobular carcinoma in situ.

BACKGROUND: Invasive lobular breast cancer (ILC) and lobular carcinoma in situ (LCIS) are characterised by loss of E-cadherin expression. However germline CDH1 mutations are rare in cases of ILC with no family history of hereditary diffuse gastric cancer (HDGC) and have not been described in women with LCIS. METHODS: We screened the CDH1 gene in 50 cases of bilateral LCIS/ILC using Sanger sequencing and MLPA. RESULTS: Sanger sequencing revealed four pathogenic germline mutations, including a novel splicing mutation (c.48+1G>A). The remaining three (c.1465insC, c.1942G>T, c.2398delC) have been previously described. All four cases had bilateral LCIS +/- ILC and no family history of gastric cancer. CONCLUSION: CDH1 germline mutations have not been previously described in women with LCIS. We have shown that germline CDH1 mutations are associated with early onset of bilateral LCIS with or without ILC in women without a family history of gastric cancer. CDH1 mutation screening should be considered in women with early onset of bilateral LCIS/ILC with no family history of HDGC.

Breast cancer metastasising to the pelvis and abdomen: what the gynaecologist needs to know.

A small proportion of breast cancers metastasise within the peritoneal cavity. With increasing breast cancer incidence rates, gynaecologists and oncologists will encounter such women more frequently. Most women with intraperitoneal breast cancer are premenopausal. Although data are limited and are likely to be subject to selection bias, the median survival of women undergoing resection appears superior to those not undergoing surgery. Furthermore, survival is broadly similar to that for women undergoing advanced ovarian cancer surgery, particularly when tumour debulking is optimal. Obtaining data via randomised trials is unlikely to be feasible and therefore we recommend prospective data collection via the establishment of an international intraperitoneal breast cancer patient registry. For individual women where survival is anticipated to be more than a few months, we suggest considering referral to a gynaecological oncology team for discussion of surgical options.

Online social network size is reflected in human brain structure.

The increasing ubiquity of web-based social networking services is a striking feature of modern human society. The degree to which individuals participate in these networks varies substantially for reasons that are unclear. Here, we show a biological basis for such variability by demonstrating that quantitative variation in the number of friends an individual declares on a web-based social networking service reliably predicted grey matter density in the right superior temporal sulcus, left middle temporal gyrus and entorhinal cortex. Such regions have been previously implicated in social perception and associative memory, respectively. We further show that variability in the size of such online friendship networks was significantly correlated with the size of more intimate real-world social groups. However, the brain regions we identified were specifically associated with online social network size, whereas the grey matter density of the amygdala was correlated both with online and real-world social network sizes. Taken together, our findings demonstrate that the size of an individual's online social network is closely linked to focal brain structure implicated in social cognition.

APC and the three-hit hypothesis.

The seminal 'two-hit hypothesis' implicitly assumes that bi-allelic tumour suppressor gene (TSG) mutations cause loss of protein function. All subsequent events in that tumour therefore take place on an essentially null background for that TSG protein. We have shown that the two-hit model requires modification for the APC TSG, because mutant APC proteins probably retain some function and the two hits are co-selected to produce an optimal level of Wnt activation. We wondered whether the optimal Wnt level might change during tumour progression, leading to selection for more than two hits at the APC locus. Comprehensive screening of a panel of colorectal cancer (CRC) cell lines and primary CRCs showed that some had indeed acquired third hits at APC. These third hits were mostly copy number gains or deletions, but could be protein-truncating mutations. Third hits were significantly less common when the second hit at APC had arisen by copy-neutral loss of heterozygosity. Both polyploid and near-diploid CRCs had third hits, and the third hits did not simply arise as a result of acquiring a polyploid karyotype. The third hits affected mRNA and protein levels, with potential functional consequences for Wnt signalling and tumour growth. Although some third hits were probably secondary to genomic instability, others did appear specifically to target APC. Whilst it is generally believed that tumours develop and progress through stepwise accumulation of mutations in different functional pathways, it also seems that repeated targeting of the same pathway and/or gene is selected in some cancers.

Experience of the use of trabectedin (ET-743, Yondelis) in 21 patients with pre-treated advanced sarcoma from a single centre.

AIMS: Trabectedin (ET-743, Yondelis) is a marine-derived alkaloid that has two actions. It binds in the minor groove of DNA resulting in a conformational change; thus potentially altering interactions with transcription factors and other DNA binding proteins and it also interacts with the transcription-coupled nucleotide excision repair machinery to induce lethal double-stranded DNA breaks. In recent phase II trials it has shown considerable activity in the treatment of sarcomas. Here the use of trabectedin in patients with advanced refractory sarcoma from a single institution is presented. MATERIALS AND METHODS: Twenty-one patients with advanced refractory sarcoma from a single UK centre were treated with trabectedin on a named patient compassionate basis programme. All patients had received prior treatment with an anthracycline, and 95% had received ifosfamide. RESULTS: The patients received a median of four cycles of treatment. Objective partial responses were seen in three patients (14%) and a further eight patients (38%) achieved durable stable disease for a median duration of 4.5 months. The estimated 3- and 6-month progression-free survival was 58.8 and 17.6%, respectively. Six patients experienced early disease progression, and four patients died while on treatment. One death was due to treatment-related toxicity. Overall the drug was relatively well tolerated, with hepatic and haematological toxicities most commonly encountered. Both necessitated delays and/or dose reductions in a proportion of patients. Other significant toxicities were nausea, vomiting and asthenia. CONCLUSION: The disease responses and durable nature of disease stabilisation seen in a proportion of our patients support the continued investigational use of this drug in the treatment of advanced soft tissue sarcomas.

A comprehensive study of chromosome 16q in invasive ductal and lobular breast carcinoma using array CGH.

We analysed chromosome 16q in 106 breast cancers using tiling-path array-comparative genomic hybridization (aCGH). About 80% of ductal cancers (IDCs) and all lobular cancers (ILCs) lost at least part of 16q. Grade I (GI) IDCs and ILCs often lost the whole chromosome arm. Grade II (GII) and grade III (GIII) IDCs showed less frequent whole-arm loss, but often had complex changes, typically small regions of gain together with larger regions of loss. The boundaries of gains/losses tended to cluster, common sites being 54.5-55.5 Mb and 57.4-58.8 Mb. Overall, the peak frequency of loss (83% cancers) occurred at 61.9-62.9 Mb. We also found several 'minimal' regions of loss/gain. However, no mutations in candidate genes (TRADD, CDH5, CDH8 and CDH11) were detected. Cluster analysis based on copy number changes identified a large group of cancers that had lost most of 16q, and two smaller groups (one with few changes, one with a tendency to show copy number gain). Although all morphological types occurred in each cluster group, IDCs (especially GII/GIII) were relatively overrepresented in the smaller groups. Cluster groups were not independently associated with survival. Use of tiling-path aCGH prompted re-evaluation of the hypothetical pathways of breast carcinogenesis. ILCs have the simplest changes on 16q and probably diverge from the IDC lineage close to the stage of 16q loss. Higher-grade IDCs probably develop from low-grade lesions in most cases, but there remains evidence that some GII/GIII IDCs arise without a GI precursor.

Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability.

Exonuclease 1 (EXO1) is a candidate gene for colorectal tumor susceptibility because it is believed to play a role in mismatch repair. There have been several studies investigating the role of EXO1 in mismatch repair but few investigating its role in causing clinical disease. In one recent study, germline variants of EXO1 were reported to be associated with predisposition to colorectal cancer in families with phenotypes similar to hereditary nonpolyposis colon cancer (HNPCC). We recently identified nine individuals from two British families with multiple cutaneous and uterine leiomyomatosis with independently arising heterozygous germline deletions of 1q42.3 approximately q43 encompassing not only FH, the multiple leiomyomatosis-associated gene, but also several flanking genes, including EXO1. We investigated these families for any indication of predisposition to colorectal cancer or other HNPCC spectrum cancers by means of detailed questionnaires, interviews, and examination of EXO1-null skin leiomyomata for microsatellite instability (MSI). No individual in these families had developed colorectal cancer or known colorectal adenomas, and none had any symptoms warranting gastrointestinal or other investigation. EXO1-null tumors showed no evidence of MSI. This study questions the functional significance of previously reported variants of EXO1 reported in HNPCC-like families and suggests that in humans there may be other as yet undiscovered proteins that have exonuclease function overlapping with that of EXO1 in DNA mismatch repair. Also of interest is the absence of phenotypic abnormality apart from multiple leiomyomatosis in any deletion carrier even though the adjacent genes RGS7, KMO, CHML, and OPN3 were also deleted.

Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at APC.

In vitro data show that the adenomatous polyposis coli (APC) protein associates with the mitotic spindle and that mouse embryonic stem cells with biallelic Apc mutations are karyotypically unstable. These findings led to suggestions that APC acts in chromosomal segregation and that APC inactivation leads to chromosomal instability (CIN). An alternative hypothesis based on allelic loss studies in colorectal adenomas proposes that CIN precedes and contributes to genetic changes at APC. We determined whether colorectal adenomas with two mutations at APC show features consistent with these models by studying 55 lesions (average size 5 mm; range 1-13 mm) from patients with familial adenomatous polyposis. A variety of methods was used depending on available material, including flow cytometry, comparative genomic hybridization, and loss of heterozygosity (LOH) analysis. Selected adenomas were assessed for proliferative activity by Ki-67 immunocytochemistry. Seventeen of 20 (85%) tumors were diploid, two were near-diploid, and one was hypotetraploid. Just one (near-diploid) tumor showed increased proliferative activity. LOH was found occasionally on chromosome 15q (2 of 49 tumors), but not on chromosome 18q (0 of 48). In 20 adenomas, LOH at APC was associated with loss at 5q but not 5p markers, with the former encompassing a minimum of 20 Mb. However, three of these lesions analyzed by comparative genomic hybridization displayed normal profiles, suggesting, together with other data, that the mechanism of LOH at APC is probably somatic recombination. Our results therefore do not support the hypothesis that CIN precedes APC mutations in tumorigenesis. Regarding the model in which APC mutations lead directly to CIN, if APC mutations do have this effect in vivo, it must be subtle. Alternatively, CIN associated with APC mutations might be essentially an in vitro phenomenon.

Methods of molecular analysis: assessing losses and gains in tumours.

The study of chromosomal aberrations has facilitated the understanding of tumorigenesis. By applying molecular genetic techniques to regions highlighted by cytogenetic study, many genes important in tumorigenesis have been identified. This review will describe the cytogenetic and molecular cytogenetic techniques used to identify these changes. The clinical information that they can provide, including diagnostic and prognostic information, will also briefly be discussed.

SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway.

Loss of chromosome 18q21 is well documented in colorectal cancer, and it has been suggested that this loss targets the DCC, DPC4/SMAD4, and SMAD2 genes. Recently, the importance of SMAD4, a downstream regulator in the TGF-beta signaling pathway, in colorectal cancer has been highlighted, although the frequency of SMAD4 mutations appears much lower than that of 18q21 loss. We set out to investigate allele loss, mutations, protein expression, and cytogenetics of chromosome 18 copy number in a collection of 44 colorectal cancer cell lines of known status with respect to microsatellite instability (MSI). Fourteen of thirty-two MSI(-) lines showed loss of SMAD4 protein expression; usually, one allele was lost and the other was mutated in one of a number of ways, including deletions of various sizes, splice site changes, and missense and nonsense point mutations (although no frameshifts). Of the 18 MSI(-) cancers with retained SMAD4 expression, four harbored missense mutations in the 3' part of the gene and showed allele loss. The remaining 14 MSI(-) lines had no detectable SMAD4 mutation, but all showed allele loss at SMAD4 and/or DCC. SMAD4 mutations can therefore account for about 50-60% of the 18q21 allele loss in colorectal cancer. No MSI(+) cancer showed loss of SMAD4 protein or SMAD4 mutation, and very few had allelic loss at SMAD4 or DCC, although many of these MSI(+) lines did carry TGFBIIR changes. Although SMAD4 mutations have been associated with late-stage or metastatic disease, our combined molecular and cytogenetic data best fit a model in which SMAD4 mutations occur before colorectal cancers become aneuploid/polyploid, but after the MSI(+) and MSI(-) pathways diverge. Thus, MSI(+) cancers may diverge first, followed by CIN(+) (chromosomal instability) cancers, leaving other cancers to follow a CIN(-)MSI(-) pathway.

Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast.

The cell-cell adhesion receptor gene E-cadherin (CDH1) is expressed by epithelial cells, in which it mediates adhesion and morphogenesis. Invasive lobular carcinoma (ILC) characteristically infiltrates diffusely as single cells; by immunohistochemistry, many of these tumours lack E-cadherin expression. In the present study we investigated various ways in which loss of function of the E-cadherin gene could occur in ILCs, namely, promoter methylation, mutation and allelic loss. We analysed 22 ILCs and found 12 (55%) E-cadherin-negative samples by immunohistochemical analysis. Methylation-specific polymerase chain reaction (PCR) showed that 17/22 (77%) of these tumours had methylation of the CDH1 promoter, including 11/12 (91%) of the E-cadherin-negative tumours. All 16 exons of E-cadherin (including intron-exon boundaries) were amplified from chromosomal DNA and screened for mutations by conformation-sensitive gel electrophoresis (CSGE). Bands with altered mobility were analysed by direct sequencing. We identified five frameshift mutations, which resulted in downstream stop codons and one splice site mutation in six different tumours (29%). Loss of heterozygosity (LOH) was assessed using microsatellite markers, and 9/18 (50%) informative tumours showed LOH. We conclude that most ILCs show genetic or epigenetic changes affecting the E-cadherin gene and that many of these tumours lack E-cadherin expression. In all cases in which there was loss of expression, this was consistent with biallelic inactivation of CDH1 by promoter methylation, mutation or allelic loss in any combination.

Two hits revisited again.

INTRODUCTION AND METHODS: Since the concept of the "two hit hypothesis" was introduced over 20 years ago, a wealth of genetic data has accumulated on the mutations found at tumour suppressor loci. Perhaps surprisingly, these data conceal large gaps in our knowledge which genetic and functional studies are beginning to uncover. The "two hit hypothesis" must be updated to take account of this new information. RESULTS AND DISCUSSION: Here, we discuss both the results of recent studies and some of the questions that they highlight. In particular, how valid are conclusions from inherited Mendelian syndromes when applied to sporadic cancers? Why is allelic loss so common and how does it occur? Are the "two hits" random or interdependent? Is abolition of protein function always optimal for tumorigenesis? Can "third hits" occur and, if so, why? How can mismatch repair deficiency and the methylator phenotype be incorporated into the "two hit" hypothesis? We suggest that the "two hit hypothesis" is not fixed but is evolving as our knowledge expands.

Comparative genomic hybridization.

Comparative genomic hybridization (CGH) is a molecular cytogenetic technique used to screen the entire genome for gains and losses of genetic material (1). It is being used increasingly in the study of cancer genetics to identify genes important in the initiation, progression, and, of particular relevance here, metastasis of tumors (2-4).One of the advantages of the technique is that the entire genome is examined in a single experiment, so there is no necessity to know the genetic region of interest prior to investigation. Once regions of gain or loss have been identified, these regions can be defined further using fluorescence in situ hybridization (FISH) (described in Chapter 14 by Goker and Shipley) or molecular genetic techniques. CGH is essentially a modified in situ hybridization. Differentially labeled test or tumor DNA (green) and reference or normal DNA (red) are cohybridized to normal metaphase spreads. Differences in the copy number between test and reference DNA are seen as differences in the ratio of green to red fluorescence intensity on the metaphase chromosomes. Images of the metaphases are captured and quantification of the fluorescence ratios performed using a digital image analysis system. Regions of chromosomal gain are seen as an increased fluorescence ratio whereas regions of loss are seen as a decrease in the fluorescence ratio. Losses are detectable when the region affected exceeds 10 Mb (5), smaller regions of gain are detected if there is high level amplification, for example a 2-Mb region that is amplified five times will be visualized (6). For each tumor, 5/210 metaphases are analyzed and an average fluorescence ratio for each chromosome obtained.

Adjuvant mitozantrone chemotherapy in advanced prostate cancer.

OBJECTIVE: To assess the role of mitozantrone, active in relapsed prostate cancer, as an adjuvant to hormonal treatment in patients with advanced prostate cancer. PATIENTS AND METHODS: Between October 1990 and May 1995, 96 patients were entered into a stratified, randomized, single-institution study of hormonal therapy with a luteinizing hormone-releasing hormone agonist and flutamide, with or without four cycles of adjuvant mitozantrone. Of these, 93 patients were evaluable and the results were analysed in June 1999. RESULTS: Patients with localized prostate cancer receiving adjuvant chemotherapy had a higher initial objective response rate (95% vs 53%, P = 0.008) and median survival (80 vs 36 months, P = 0.04) than patients who were treated with hormonal therapy alone. There was no advantage to adjuvant chemotherapy in patients with metastatic prostate cancer. There were insignificant advantages to chemotherapy in overall response rates (55% vs 39%, P = 0.3) and PSA responses (82% vs 64%, P = 0.11). There was no difference between the patient groups in time to treatment failure. CONCLUSION: There was a survival advantage in using adjuvant mitozantrone in patients with locally advanced prostate cancer. Although the study comprised relative few patients, the follow-up period was long and the advantage significant. We recommend that the study be extended to include more patients.