PREDICT-GTN 2: Two-factor streamlined models match FIGO performance in gestational trophoblastic neoplasia.

OBJECTIVE: The International Federation of Gynecology and Obstetrics (FIGO) scoring system uses the sum of eight risk-factors to predict single-agent chemotherapy resistance in Gestational Trophoblastic Neoplasia (GTN). To improve ease of use, this study aimed to generate: (i) streamlined models that match FIGO performance and; (ii) visual-decision aids (nomograms) for guiding management. METHODS: Using training (n = 4191) and validation datasets (n = 144) of GTN patients from two UK specialist centres, logistic regression analysis generated two-factor models for cross-validation and exploration. Performance was assessed using true and false positive rate, positive and negative predictive values, Bland-Altman calibration plots, receiver operating characteristic (ROC) curves, decision-curve analysis (DCA) and contingency tables. Nomograms were developed from estimated model parameters and performance cross-checked upon the training and validation dataset. RESULTS: Three streamlined, two-factor models were selected for analysis: (i) M1, pre-treatment hCG + history of failed chemotherapy; (ii) M2, pre-treatment hCG + site of metastases and; (iii) M3, pre-treatment hCG + number of metastases. Using both training and validation datasets, these models showed no evidence of significant discordance from FIGO (McNemar's test p > 0.78) or across a range of performance parameters. This behaviour was maintained when applying algorithms simulating the logic of the nomograms. CONCLUSIONS: Our streamlined models could be used to assess GTN patients and replace FIGO, statistically matching performance. Given the importance of imaging parameters in guiding treatment, M2 and M3 are favoured for ongoing validation. In resource-poor countries, where access to specialist centres is problematic, M1 could be pragmatically implemented. Further prospective validation on a larger cohort is recommended.

Patients' experience of menopausal symptoms post-chemotherapy treatment for gestational trophoblastic neoplasia.

PURPOSE: We aimed to explore patient's experience of chemotherapy-induced menopausal symptoms; to ascertain how patients tried to alleviate their symptoms and how health professionals supported them in order to identify current unmet needs. METHODS: We designed a retrospective cross-sectional exploratory study of a sample of 11 women who received multi-agent combination chemotherapy for Gestational Trophoblastic Neoplasia. Postal surveys using the Greene Climacteric Scale (GCS) questionnaire followed up by semi-structured telephone interviews were used. Framework analysis technique was used to generate descriptions of patient's experiences. RESULTS: Symptoms of feeling tired or lacking in energy, loss of interest in sex, muscle and joint pains and difficulty in concentrating affected participants the most. The menopausal symptoms appear to be temporary; symptoms such as hot flushes and night sweats seem to subside with resumption of menses. Others are more gradual with some evidence that mental health takes longer to recover. Regarding potential symptoms, some women do not retain the information given to them at discharge following end of treatment, which GTD services need to take into consideration when supporting patients. CONCLUSION: Patients need to be more optimally prepared for post-chemotherapy recovery with each patient's needs and support being individually tailored. How information is discussed and disseminated needs improving to ensure patients retain the information they receive at discharge. Recommendations include the creation of menopause information booklet, alongside further developing virtual nurse-led follow up clinics post chemotherapy.

High HIV prevalence in gestational trophoblastic neoplasia patients.

OBJECTIVE: To assess the HIV prevalence in patients diagnosed with gestational trophoblastic neoplasia (GTN). DESIGN: A retrospective single centre cohort study. METHODS: A database from the Sheffield Trophoblastic Disease Centre (STDC), Sheffield, UK was searched between 1st January 2015 and 31st December 2021. A total of 3,591 patients were referred to STDC with a diagnosis of gestational trophoblastic disease (GTD), of which 221 (6.2%) were treated for GTN. The prevalence of HIV-positive tests in GTN patients was assessed. RESULTS: HIV testing was performed in 93% GTN patients ( n  = 205/221). Overall, 1.3% of GTN patients ( n  = 3/221) were HIV-positive, involving two known HIV-positive patients and one new diagnosis. This equates to a HIV prevalence of 14 : 1000, which is ∼7 to 9× higher than the HIV prevalence in Sheffield (1.9 per 1000) and Yorkshire and Humber (1.5 per 1000). CONCLUSION: Given the extremely high HIV prevalence in our population, 'opt out' HIV testing is recommended within our specialist trophoblastic centre for all referred GTD and GTN patients. There is little reason to suspect that the prevalence of HIV-positive patients is any lower in the cohort of GTD patients referred to specialist trophoblastic centres for hCG screening alone, without requiring chemotherapy, particularly considering that most GTN arises from GTD.

Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010).

PURPOSE: Approximately 10% to 15% of triple-negative breast cancers (TNBC) have deleterious mutations in BRCA1 and BRCA2 and may benefit from PARP inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related (ATR) protein. This phase II study examined the activity of the combination of PARP inhibitor, olaparib, and ATR inhibitor, ceralasertib (AZD6738), in patients with advanced TNBC. PATIENTS AND METHODS: Patients with TNBC on most recent biopsy who had received 1 or 2 lines of chemotherapy for advanced disease or had relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300 mg twice a day continuously and celarasertib 160 mg on days 1-7 on a 28-day cycle until disease progression. The primary endpoint was confirmed objective response rate (ORR). Tissue and plasma biomarker analyses were preplanned to identify predictors of response. RESULTS: 70 evaluable patients were enrolled. Germline BRCA1/2 mutations were present in 10 (14%) patients and 3 (4%) patients had somatic BRCA mutations. The confirmed ORR was 12/70; 17.1% (95% confidence interval, 10.4-25.5). Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumors with functional homologous recombination deficiency by RAD51 foci. CONCLUSIONS: The response rate to olaparib and ceralasertib did not meet prespecified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to olaparib monotherapy.

Efficacy analysis of single-agent carboplatin AUC4 2-weekly as second-line therapy for methotrexate-resistant (MTX-R) low risk gestational trophoblastic neoplasia (GTN).

BACKGROUND: Approximately one-third of patients with low-risk Gestational Trophoblastic Neoplasia (WHO 0-6) develop methotrexate-resistance (MTX-R). In the UK, subsequent treatment with either actinomycin-D (ActD) or multi-agent combination chemotherapy has depended on whether the hCG was above or below an hCG threshold. To reduce exposure to combination chemotherapy (CC), over the years the UK service has raised this threshold as well as using single-agent carboplatin AUC6 3-weekly at MTX-R instead of CC. Updated results for carboplatin demonstrate an 86% complete hCG response (hCG CR) but associated with haematological dose-limiting toxicity. METHODS: In 2017, single-agent carboplatin became the national standard second-line treatment following MTX-R at hCG of >3000 IU/L. Carboplatin was changed to two-weekly AUC4 scheduling and continued until normal hCG plus 3 consolidation cycles. For patients failing to respond, CC (Etoposide-Actinomycin-D or EMA-CO) was introduced. RESULTS: 22 evaluable patients with a median hCG at MTX-R of 10,147 IU/L (IQR 5527-19,639) received carboplatin AUC4 2-weekly (median no. of cycles = 6, IQR 2-8). Of these, 36% achieved a hCG CR. All 14 non-CR patients were cured with subsequent CC; 11 and 2 patients with 3rd line and 4th line CC respectively and 1 patient following 5th line CC and hysterectomy. Overall survival remains 100%. CONCLUSION: Carboplatin is not sufficiently active in the second-line treatment of low-risk MTX-resistant GTN. New strategies are required to increase hCG CR and spare more toxic CC regimens.

Flat-dose versus weight or body surface area-based methotrexate dosing in low-risk gestational trophoblastic neoplasia.

BACKGROUND: Single-agent methotrexate (MTX) is commonly used as first-line treatment for low-risk gestational trophoblastic neoplasia (LR-GTN), although no international consensus exists on the optimal treatment regimen to maximise complete hCG response (CR) and minimise relapse rates. Current regimens differ in the route of administration, dose scheduling, and use of flat-dose, body surface area (BSA)- or weight-based dosing. In the UK a methotrexate-folinic acid (MTX-FA) 8-day 50 mg intramuscular flat-dose regimen is used, with 15 mg oral folinic acid rescue. In LR-GTN patients, we aim to determine the effect of MTX dose adjustment by BSA and weight upon chemotherapy response and disease relapse. METHODS: Between January 1973 and August 2020, 935 LR-GTN patients treated with first-line MTX-FA were identified from a single UK specialist trophoblastic centre. Of these, 364 were included, of which 178 (49%) had a CR to first-line MTX-FA. Subgroup analyses were performed upon: (i) patients who changed chemotherapy due to MTX toxicity (n = 33); and (ii) patients with a FIGO score of 5-6 (n = 85). Logistic regression analysis explored the relationship between BSA or weight adjusted MTX dosing and: (i) CR to first-line chemotherapy; (ii) incidence of disease relapse. Linear regression analyses assessed the correlation of BSA and weight with the number of MTX-FA cycles required to achieve CR. RESULTS: In LR-GTN patients, BSA and weight adjusted MTX-FA dosing did not influence CR to first-line chemotherapy or the incidence of disease relapse. The number of MTX cycles required to achieve CR was not associated with BSA or weight. These findings were maintained in a subgroup analysis of FIGO 5-6 patients. The incidence of MTX toxicity was not influenced by BSA or weight. CONCLUSIONS: In the treatment of LR-GTN, dose individualisation using BSA or weight is not required, and fixed dosing continues to be preferred as the UK standard.

PREDICT-GTN 1: Can we improve the FIGO scoring system in gestational trophoblastic neoplasia?

Gestational trophoblastic neoplasia (GTN) patients are treated according to the eight-variable International Federation of Gynaecology and Obstetrics (FIGO) scoring system, that aims to predict first-line single-agent chemotherapy resistance. FIGO is imperfect with one-third of low-risk patients developing disease resistance to first-line single-agent chemotherapy. We aimed to generate simplified models that improve upon FIGO. Logistic regression (LR) and multilayer perceptron (MLP) modelling (n = 4191) generated six models (M1-6). M1, all eight FIGO variables (scored data); M2, all eight FIGO variables (scored and raw data); M3, nonimaging variables (scored data); M4, nonimaging variables (scored and raw data); M5, imaging variables (scored data); and M6, pretreatment hCG (raw data) + imaging variables (scored data). Performance was compared to FIGO using true and false positive rates, positive and negative predictive values, diagnostic odds ratio, receiver operating characteristic (ROC) curves, Bland-Altman calibration plots, decision curve analysis and contingency tables. M1-6 were calibrated and outperformed FIGO on true positive rate and positive predictive value. Using LR and MLP, M1, M2 and M4 generated small improvements to the ROC curve and decision curve analysis. M3, M5 and M6 matched FIGO or performed less well. Compared to FIGO, most (excluding LR M4 and MLP M5) had significant discordance in patient classification (McNemar's test P < .05); 55-112 undertreated, 46-206 overtreated. Statistical modelling yielded only small gains over FIGO performance, arising through recategorisation of treatment-resistant patients, with a significant proportion of under/overtreatment as the available data have been used a priori to allocate primary chemotherapy. Streamlining FIGO should now be the focus.

Observational cohort study in older women with early breast cancer: Use of radiation therapy and impact on health-related quality of life and mortality.

BACKGROUND: Radiotherapy reduces in-breast recurrence risk in early breast cancer (EBC) in older women. This benefit may be small and should be balanced against treatment effect and holistic patient assessment. This study described treatment patterns according to fitness and impact on health-related quality-of-life (HRQoL). METHODS: A multicentre, observational study of EBC patients aged ≥ 70 years, undergoing breast-conserving surgery (BCS) or mastectomy, was undertaken. Associations between radiotherapy use, surgery, clinico-pathological parameters, fitness based on geriatric parameters and treatment centre were determined. HRQoL was measured using the European Organisation for the Research and Treatment of Cancer (EORTC) questionnaires. RESULTS: In 2013-2018 2811 women in 56 UK study centres underwent surgery with a median follow-up of 52 months. On multivariable analysis, age and tumour risk predicted radiotherapy use. Among healthier patients (based on geriatric assessments) with high-risk tumours, 534/613 (87.1%) having BCS and 185/341 (54.2%) having mastectomy received radiotherapy. In less fit individuals with low-risk tumours undergoing BCS, 149/207 (72.0%) received radiotherapy. Radiotherapy effects on HRQoL domains, including breast symptoms and fatigue were seen, resolving by 18 months. CONCLUSION: Radiotherapy use in EBC patients ≥ 70 years is affected by age and recurrence risk, whereas geriatric parameters have limited impact regardless of type of surgery. There was geographical variation in treatment, with some fit older women with high-risk tumours not receiving radiotherapy, and some older, low-risk, EBC patients receiving radiotherapy after BCS despite evidence of limited benefit. The impact on HRQoL is transient.

Bridging The Age Gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer.

BACKGROUND: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy. METHODS: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage. RESULTS: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19-0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20-0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08-0.49];BCSS: HR 0.12 [95% CI 0.03-0.44]).Transient negative quality-of-life impacts were observed. CONCLUSIONS: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient. TRIAL REGISTRATION: ISRCTN 46099296.

Treatment of low-risk gestational trophoblastic neoplasia.

Low-risk gestational trophoblastic neoplasia (GTN), defined as FIGO/WHO score 0-6, is highly curable with an overall survival rate, which is approximately 100%. For most low-risk GTN patients, first-line single-agent chemotherapy with either methotrexate or actinomycin-D is recommended with overall complete human chorionic gonadotrophin (hCG) response rates of 60%-90% in mostly retrospective, non-randomised studies. The few randomised trials that exist are not appropriately powered or designed to define the optimal first-line treatment. Approximately 25%-30% of low-risk patients will develop resistance to initial single-agent chemotherapy with an increase in the FIGO score, a diagnosis of choriocarcinoma, higher pre-treatment hCG and the presence of metastatic disease being associated with an increase in the risk of resistance. The optimal treatment of patients scoring WHO 5 and 6 remains poorly defined given that approximately 70%-80% of these patients develop resistance to first-line single-agent chemotherapy, and there is an urgent need to refine the FIGO/WHO scoring system so that these patients can be identified for more intensive therapy from the outset. Despite this, almost all low-risk patients who experience treatment failure with first-line monotherapy will be cured with either sequential single-agent chemotherapy or multiagent chemotherapy with or without surgery. Given the associated increased short and longer-term toxicities associated with multi-agent chemotherapy, promising strategies to reduce the exposure of women to combination chemotherapy in low-risk disease have been investigated, including the use of carboplatin and immune check-point inhibitors. Further evaluation is required to define optimal patient selection, particularly with the use of immunotherapeutic agents given their significant increased costs and lack of longer-term safety data. Although there is a clear need to revise the FIGO/WHO (2000) scoring system, consistent international use of this is recommended to facilitate the comparison of data along with future focus in the development of international collaborative translational and clinical research, including randomised controlled trials.

Computed tomography chest imaging offers no advantage over chest X-ray in the initial assessment of gestational trophoblastic neoplasia.

BACKGROUND: The International Federation of Gynaecology and Obstetrics (FIGO) score identifies gestational trophoblastic neoplasia (GTN) patients as low- or high-risk of single-agent chemotherapy resistance (SACR). Computed tomography (CT) has greater sensitivity than chest X-ray (CXR) in detecting pulmonary metastases, but effects upon outcomes remain unclear. METHODS: Five hundred and eighty-nine patients underwent both CXR and CT during GTN assessment. Treatment decisions were CXR based. The number of metastases, risk scores, and risk category using CXR versus CT were compared. CT-derived chest assessment was evaluated as impact upon treatment decision compared to patient outcome, incidence of SACR, time-to-normal human chorionic gonadotrophin hormone (TNhCG), and primary chemotherapy resistance (PCR). RESULTS: Metastasis detection (p < 0.0001) and FIGO score (p = 0.001) were higher using CT versus CXR. CT would have increased FIGO score in 188 (31.9%), with 43 re-classified from low- to high-risk, of whom 23 (53.5%) received curative single-agent chemotherapy. SACR was higher when score (p = 0.044) or risk group (p < 0.0001) changed. Metastases on CXR (p = 0.019) but not CT (p = 0.088) lengthened TNhCG. Logistic regression analysis found no difference between CXR (area under the curve (AUC) = 0.63) versus CT (AUC = 0.64) in predicting PCR. CONCLUSIONS: CT chest would improve the prediction of SACR, but does not influence overall treatment outcome, TNhCG, or prediction of PCR. Lower radiation doses and cost mean ongoing CXR-based assessment is recommended.

Bridging the Age Gap in breast cancer: Impact of chemotherapy on quality of life in older women with early breast cancer.

INTRODUCTION: Older patients with early breast cancer (EBC) derive modest survival benefit from chemotherapy but have increased toxicity risk. Data on the impact of chemotherapy for EBC on quality of life in older patients are limited, but this is a key determinant of treatment acceptance. We aimed to investigate its effect on quality of life in older patients enrolled in the Bridging the Age Gap study. MATERIALS AND METHODS: A prospective, multicentre, observational study of EBC patients ≥70 years old was conducted in 2013-2018 at 56 UK hospitals. Demographics, patient, tumour characteristics, treatments and adverse events were recorded. Quality of life was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaires (EORTC-QLQ) C30, BR23 and ELD 15 plus the Euroqol-5D (eq-5d) over 24 months and analysed at each time point using baseline adjusted linear regression analysis and propensity score-matching. RESULTS: Three thousand and four hundred sixteen patients were enrolled in the study; 1520 patients undergoing surgery and who had high-risk EBC were included in this analysis. 376/1520 (24.7%) received chemotherapy. At 6 months, chemotherapy had a significant negative impact in several EORTC-QLQ-C30 domains, including global health score, physical, role, social functioning, cognition, fatigue, nausea/vomiting, dyspnoea, appetite loss, diarrhoea and constipation. Similar trends were documented on other scales (EORTC-QLQ-BR23, EORTC-QLQ-ELD15 and EQ-5D-5L). Its impact was no longer significant at 18-24 months in unmatched and matched cohorts. CONCLUSIONS: The negative impact of chemotherapy on quality-of-life is clinically and statistically significant at 6 months but resolves by 18 months, which is crucial to inform decision-making for older patients contemplating chemotherapy. TRIAL REGISTRATION NUMBER ISRCTN: 46099296.

M-EA (methotrexate, etoposide, dactinomycin) and EMA-CO (methotrexate, etoposide, dactinomycin / cyclophosphamide, vincristine) regimens as first-line treatment of high-risk gestational trophoblastic neoplasia.

High-risk gestational trophoblastic neoplasia (GTN) is highly chemosensitive with an excellent prognosis with treatment. Historically in the United Kingdom, the high-risk regimens used have been M-EA (methotrexate, etoposide, dactinomycin) (Sheffield) and EMA-CO (methotrexate, etoposide, dactinomycin / cyclophosphamide, vincristine) (Charing Cross, London) with prior published data suggesting no difference in survival between these. Our Sheffield treatment policy changed in 2014, switching from M-EA to EMA-CO, aiming to reduce time in hospital, and harmonise UK practice. We aimed to report the toxicities, response rates and survival outcomes for 79 patients with high-risk GTN treated in the first-line setting with either M-EA (n = 59) or EMA-CO (n = 20) from 1998 to 2018. Median duration of treatment was similar (M-EA, 17.3 weeks (IQR 13.9-22.6) and 17.6 weeks (IQR 13.4-20.7) with EMA-CO. For M-EA, overall human chorionic gonadotrophin (hCG) complete response (CR) rate was 84.7% (n = 50/59). Two patients died of drug-resistant disease after several lines of multiagent chemotherapy; overall survival is 96.6% (median follow-up 10.4 years). For EMA-CO, overall hCG CR rate was 70%, overall survival is 100% (median follow-up 4 years). In our experience, patients treated with EMA-CO experienced an apparent increased incidence of neutropenia, non-neutropenic Grade 3-4 infection, peripheral neuropathy and more treatment delays and nights in hospital. Granulocyte-colony stimulating factor, after both EMA and CO arms, titrated to baseline neutrophil count improved the toxicity profile. Both treatment regimens are associated with excellent prognosis; selection of regimen may be further guided by individual patients' personal, social and family circumstances. There is further rationale to explore whether these regimens can be refined, such as 2-weekly EMA, to optimise patient experience and reduce toxicity while maintaining efficacy.

Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial.

BACKGROUND: Circulating tumour DNA (ctDNA) testing might provide a current assessment of the genomic profile of advanced cancer, without the need to repeat tumour biopsy. We aimed to assess the accuracy of ctDNA testing in advanced breast cancer and the ability of ctDNA testing to select patients for mutation-directed therapy. METHODS: We did an open-label, multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals. Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status 0-2. Patients had completed at least one previous line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: cohort A comprised patients with ESR1 mutations (treated with intramuscular extended-dose fulvestrant 500 mg); cohort B comprised patients with HER2 mutations (treated with oral neratinib 240 mg, and if oestrogen receptor-positive with intramuscular standard-dose fulvestrant); cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant); and cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg). Each cohort had a primary endpoint of confirmed objective response rate. For cohort A, 13 or more responses among 78 evaluable patients were required to infer activity and three or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete and long-term follow-up is ongoing. This trial is registered with ClinicalTrials.gov, NCT03182634; the European Clinical Trials database, EudraCT2015-003735-36; and the ISRCTN registry, ISRCTN16945804. FINDINGS: Between Dec 21, 2016, and April 26, 2019, 1051 patients registered for the study, with ctDNA results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 96-99% (n=800, kappa 0·89-0·93). Sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI 83-98) overall and 98% (87-100) with contemporaneous biopsies. In all cohorts, combined median follow-up was 14·4 months (IQR 7·0-23·7). Cohorts B and C met or exceeded the target number of responses, with five (25% [95% CI 9-49]) of 20 patients in cohort B and four (22% [6-48]) of 18 patients in cohort C having a response. Cohorts A and D did not reach the target number of responses, with six (8% [95% CI 3-17]) of 74 in cohort A and two (11% [1-33]) of 19 patients in cohort D having a response. The most common grade 3-4 adverse events were raised gamma-glutamyltransferase (13 [16%] of 80 patients; cohort A); diarrhoea (four [25%] of 20; cohort B); fatigue (four [22%] of 18; cohort C); and rash (five [26%] of 19; cohort D). 17 serious adverse reactions occurred in 11 patients, and there was one treatment-related death caused by grade 4 dyspnoea (in cohort C). INTERPRETATION: ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment. FUNDING: Cancer Research UK, AstraZeneca, and Puma Biotechnology.

When to stop human chorionic gonadotrophin (hCG) surveillance after treatment with chemotherapy for gestational trophoblastic neoplasia (GTN): A national analysis on over 4,000 patients.

OBJECTIVE: To determine the optimal duration of human chorionic gonadotrophin (hCG) surveillance following treatment for low and high risk gestational trophoblastic neoplasia (GTN) and establish whether the current surveillance protocol that recommends life-long hCG monitoring requires revision. METHODS: A population-based cohort study was undertaken using a national registry, comprising patients from both tertiary trophoblastic disease treatment units in the UK (London and Sheffield). All patients who received chemotherapy for low or high risk GTN in the UK between 1958 and 2014 in London and 1973 and 2015 in Sheffield (n = 4201) were included in the study. Patients with placental site trophoblastic tumours and epithelioid trophoblastic tumours were excluded due to their distinct clinical behavior, treatment and follow-up requirements. The risk of recurrence with time following completion of chemotherapy for low or high risk GTN was measured. RESULTS: The overall risk of relapse in this national cohort of 4201 patients was 4.7% (198/4201) with a median time to recurrence of 117.5 days (range 9 days to 6.54 years). The greatest risk of recurrence occurred in the first year after completing treatment for either low or high risk GTN measuring 72.7% (n = 112) or 86.4% (n = 38), respectively. The subsequent recurrence risk reduced over time with none observed beyond 7 years. CONCLUSIONS: The absence of any recurrences beyond seven years following completion of chemotherapy for GTN indicates that the UK policy of life-long hCG surveillance is unnecessary. Our revised conservative protocol recommends stopping after 10 years.

Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours.

BACKGROUND: Placental-site trophoblastic (PSTT) and epithelioid trophoblastic tumours (ETT) are the rarest malignant forms of gestational trophoblastic disease (GTD). Our prior work demonstrated that an interval of ≥48 months from the antecedent pregnancy was associated with 100% death rate, independent of the stage. Here, we assess whether modified treatments for these patients have increased survival and identify new prognostic factors. METHODS: The United Kingdom GTD database was screened to identify all PSTT/ETT cases diagnosed between 1973 and 2014. Data and survival outcomes from our prior patient cohort (1976-2006) were compared to our new modern cohort (2007-2014), when intensified treatments were introduced. RESULTS: Of 54,743 GTD patients, 125 (0.23%) were diagnosed with PSTT and/or ETT. Probability of survival at 5 and 10 years following treatment was 80% (95% CI 72.8-87.6%) and 75% (95% CI 66.3-84.3%), respectively. Univariate analysis identified five prognostic factors for reduced overall survival (age, FIGO stage, time since antecedent pregnancy, hCG level, mitotic index) of which stage IV disease (HR 6.18, 95% CI 1.61-23.81, p = 0.008) and interval ≥48 months since antecedent pregnancy (HR 14.57, 95% CI 4.17-50.96, p < 0.001) were most significant on multivariable analysis. No significant differences in prognostic factors were seen between the old and new patient cohort. However, the new cohort received significantly more cisplatin-based and high-dose chemotherapy, and patients with an interval ≥48 months demonstrated an improved median overall survival (8.3 years, 95% CI 1.53-15.1, versus 2.6 years, 95% CI 0.73-4.44, p = 0.·005). CONCLUSION: PSTT/ETT with advanced FIGO stage or an interval ≥48 months from their last known pregnancy have poorer outcomes. Platinum-based and high-dose chemotherapy may help to improve survival in poor-prognosis patients.

Systematic review of health-related quality of life and patient-reported outcome measures in gestational trophoblastic disease: a parallel synthesis approach.

Gestational trophoblastic disease is a rare complication of pregnancy that can develop into cancer. Medical outcomes of gestational trophoblastic disease are well researched, but the effect of the disease on health-related quality of life (HRQOL) requires attention if care is to be improved. This systematic review was designed to establish the effect of gestational trophoblastic disease and its treatment on HRQOL and to identify the appropriateness of HRQOL measures. Quantitative studies found HRQOL in long-term survivors of gestational trophoblastic disease to be at or above population norms. The disease had a negative effect on HRQOL for patients who experienced physical, psychological, and social sequelae related to the condition. Clinically significant levels of anxiety, depression, sexual dysfunction, and fertility-related distress were found in these patients. The results should be treated with caution because the evidence base was limited to small heterogeneous samples, data were retrospective, and a range of measures was used. Within qualitative studies on HRQOL for survivors of gestational trophoblastic disease, new conditions emerged, including nerve damage, fatigue, amenorrhoea, and grief. These areas are not captured in existing patient-reported outcome measures, and the content might not be valid for this population. Further qualitative research might lead to the development of a specific patient-reported outcome measure for gestational trophoblastic disease, providing reliable, meaningful, and valid assessments, and allowing longitudinal data to be obtained.

Management and Outcomes of Patients with Stage I and IlIl Low-Risk Gestational Trophoblastic Neoplasia Treated in Sheffield, UK, from 1997-2006.

OBJECTIVE: To review the outcome of patients treated for low-risk gestational trophoblastic neoplasia (GTN) over a 10-year period with the particular aim of assessing response to treatment in Stages I and III disease. Approximately 90% of women requiring treatment for GTN have low-risk disease. Methotrexate is the treat- ment of choice in the UK and achieves complete response rates of 50% and 90%. STUDY DESIGN: A retro- spective review of management and outcomes of patients treated for low-risk GTN at the Trophoblastic Disease Centre, Sheffield, UK, from 1997 to 2006. RESULTS: Overall 280 patients were treated for low- risk GTN during this time; 8.6% had stage III disease. Single-agent methotrexate was used as first-line therapy in 99% of cases, with a remission rate of 56%. There was no significant difference (p=0.67) in the complete response rate after first-line methotrexate between those with stage I and those with stage III disease. CONCLUSION: The overall cure rate for women with low-risk GTN was high (99.6%), and the complete response rate after first-line management was not sig- nificantly different between stages I and III disease.

The Role of Computed Tomography Scanning of the Thorax in the Initial Assessment of Gestational Trophoblastic Neoplasia.

OBJECTIVE: The aim of this study was to determine whether lesions found on computed tomography (CT) imaging of the thorax would affect FIGO (International Federation of Gynecology and Obstetrics) 2000 risk score and/or alter clinical management. METHODS: The Sheffield Trophoblastic Disease database was searched for all new patients registered for staging/scoring investigations between January 1, 2006, and June 30, 2010. The FIGO 2000 score was noted and then recalculated using information from CT scan reports. Where a change of risk score would have affected a patient's management, the case notes were further reviewed. RESULTS: 191 patients had undergone both modalities of imaging. Using standard FIGO scoring, 169 and 22 patients were noted to be at low and high risk, respectively. Using information from CT imaging, only a further 20 patients would have been reclassified as high risk. Fifteen of these "new" high-risk patients required salvage treatment with intravenous chemotherapy; all were cured. CONCLUSIONS: With no potential advantage in terms of patient outcome and significantly increased radiation dose, there is little justification for routine CT imaging of the thorax in the initial assessment of new patients with gestational trophoblastic neoplasia.

Neoadjuvant chemotherapy with or without zoledronic acid in early breast cancer--a randomized biomarker pilot study.

PURPOSE: To investigate the short-term biologic effects of neoadjuvant chemotherapy +/- zoledronic acid (ZOL) in invasive breast cancer. EXPERIMENTAL DESIGN: Forty patients were randomized to receive a single 4 mg infusion of ZOL 24 hours after the first cycle of FE100C chemotherapy, or chemotherapy alone. Randomization was stratified for tumor stage, ER, HER2, and menopausal status. All patients had repeat breast core biopsy at day 5 (D5) ± day 21 (D21). Effects on apoptotic index, proliferation (Ki67), growth index, surrogate serum markers of angiogenesis (VEGF), and serum reproductive hormones within the TGFß family (activin-A, TGFß1, inhibin-A, and follistatin) were evaluated and compared. RESULTS: Baseline clinicopathologic characteristics were well balanced. Cell growth index (increased apoptosis and reduced proliferation) fell at D5 in both groups but recovered more rapidly with chemotherapy + ZOL compared with chemotherapy alone by D21 (P = 0.006). At D5, a greater reduction in serum VEGF occurred with chemotherapy + ZOL compared with chemotherapy: median percentage change -23.8% [interquartile range (IQR): -32.9 to -15.8] versus -8.4% (IQR: -27.3 to +8.9; P = 0.02), but these effects were lost by D21. Postmenopausal women showed a decrease in follistatin levels from baseline in the chemotherapy + ZOL group at D5 and D21, compared with chemotherapy alone (P(interaction) = 0.051). CONCLUSIONS: In this pilot study, short-term changes in biomarkers suggest potentially relevant interactions between tumor biology, chemotherapy, modification of the bone microenvironment, and the endocrine status of the host. Larger studies with more frequent dosing of zoledronic acid are needed to assess these complex interactions more thoroughly.