• P-061Real-world experiences of use of aflibercept in patients with stage IV colorectal cancer in the North-West of England

      Flaum, Nicola; Kurup, Roopa; Tong, D; Alchawaf, Alia; Lau, S; Harle, Amelie S; Hajri, R; Williamson, D; Papaxoinos, G; Mullamitha, Saifee A; et al. (2016-06-21)
    • P2.05-058 Blood biomarkers of inflammation, tumor burden and proliferation predict radiotherapy response and toxicity in lung cancer.

      Salem, Ahmed; Mistry, H; Becken, Alison; Hodgson, Clare; Koh, Pek K; Dean, Emma J; Priest, Lynsey; Dive, Caroline; Renehan, Andrew G; Faivre-Finn, Corinne; et al. (2017-01)
    • P27(KIP1) expression indicates that steroid receptor-positive cells are a non-proliferating, differentiated subpopulation of the normal human breast epithelium.

      Clarke, Robert B; Howell, Anthony; Potten, Christopher S; Anderson, Elizabeth; Clinical Research Department, Christie Hospital, M20 4BX, Manchester, UK. (2000-09)
      To test the hypothesis that steroid receptor-expressing cells are derived from the proliferative population, we examined expression of the p27(KIP1) inhibitor of cyclin-dependent kinase activity (a differentiation marker) while tracking the fate of proliferating cells in normal human breast tissue implanted into athymic nude mice using tritiated thymidine [3H]-dT. We identified a small number of cells that appeared to have divided just once before switching on p27(KIP1) expression. p27(KIP1)+ve cells also expressed steroid receptors, but not the Ki67 proliferation-associated antigen. These data support the hypothesis that steroid receptor-expressing cells are a differentiated population within the normal human breast epithelium.
    • P3.02c-003 TAX-TORC: The novel combination of weekly paclitaxel and the dual mTORC1/2 inhibitor AZD2014 for the treatment of squamous NSCLC.

      Krebs, Matthew G; Spicer, J; Steele, N; Talbot, D; Brada, M; Wilson, R; Jones, R; Basu, B; Dawes, J; Parmar, M; et al. (2017-01)
    • p53 and related proteins in epithelial ovarian cancer.

      Sengupta, P S; McGown, Alan T; Bajaj, V; Blackhall, Fiona H; Swindell, Ric; Bromley, Michael; Shanks, Jonathan H; Ward, Timothy H; Buckley, C H; Reynolds, K; et al. (2000-12)
      We conducted a retrospective immunohistochemical evaluation of the prognostic significance of the expression of p53 and the related proteins Bax, Bcl-2, growth arrest and DNA damage (Gadd45), murine double minute 2 (Mdm2) and p21(WAF1/CIP1) in chemonaive tumours taken from 66 patients with ovarian cancer. Ki-67 expression (a marker of cell proliferation) was also evaluated immunohistochemically, while apoptosis within malignant cells was determined with the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL) assay. The expression of each of the following proteins was significantly associated in the tumours (P < 0.05 unless otherwise stated): Bax with Bcl-2 (P < 0.01); Bax with Mdm2; p21(WAF1/CIP1) with Gadd45 (P < 0.01); p21(WAF1/CIP1) with p53; p53 with Mdm2. Univariate analysis showed that expression of p53, Bax, bulk residual disease and International Federation of Gynecology and Obstetricians (FIGO) stage were all strongly correlated with response to chemotherapy (P < 0.01). Similarly, the FIGO stage and Ki-67 expression (P < 0.01), as well as pathological subtype and bulk residual disease (P < 0.05), were prognostic factors for disease progression. The FIGO stage and Ki-67 expression were significant prognostic factors for overall survival (P < 0.01), with Gadd45 expression and pathological subtype also significant (P < 0.05) in a univariate analysis. Multivariate analysis for response to chemotherapy showed that expression of p53, Bax and FIGO stage were all independent prognostic factors (P < 0.01). The FIGO stage was the most important independent prognostic factor for progression and survival on multivariate analysis (P < 0.01). However, Ki-67 expression was also an independent prognostic factor for disease progression (P < 0.05) and approached significance for survival (P = 0.055). Taken together, these data suggest that determination of Ki-67 expression could supplement established prognostic factors.
    • p53 overexpression as a marker of malignancy in gastric biopsies.

      Starzynska, T; Marsh, P J; Stern, Peter L; Department of Gastroenterology, Medical Pomeranian Academy, Szczecin, Poland. (1993-12)
      Inactivation of the p53 tumour-suppressor gene is the commonest genetic abnormality in human cancers. This results in a conformational change in the p53 protein, and a consequent prolongation in its half-life; thereby permitting the identification of p53 immunoreactivity in malignant cells. Such reactivity is observed in up to 57% of gastric carcinomas, and is a proven indicator of poor prognosis. We have investigated the use of p53 immunohistochemistry in the diagnosis of malignancy in pre-operative gastric biopsy specimens. Using a three-stage immunoperoxidase technique, p53 expression was examined in 117 gastric biopsies obtained during flexible upper gastrointestinal endoscopy: 80 of these biopsies were from known gastric carcinomas, 20 from benign gastric disorders and 17 from normal gastric mucosa. Of the gastric cancers 40% (n = 32) exhibited overexpression of p53. No reactivity was observed in any of the biopsies of gastric ulcers, polyps or normal mucosa. The expression of p53 by gastric carcinomas improved the diagnostic accuracy of conventional histopathology from 86% to 92.5%; with 5% of biopsies incorrectly diagnosed and 2.5% of an equivocal appearance. These results demonstrate that the detection of p53 is a highly specific marker of gastric malignancy, and that such a technique can easily be performed on biopsies obtained at endoscopy.
    • PACIFIC subgroup analysis: pneumonitis in stage III, unresectable NSCLC patients treated with durvalumab vs. placebo after CRT

      Vansteenkiste, J; Naidoo, J; Faivre-Finn, Corinne; Ozguroglu, M; Villegas, A; Daniel, D; Murakami, S; Hui, R; Lee, K; Cho, BC; et al. (2018)
    • PACIFIC-6: A phase II study of durvalumab after sequential chemoradiotherapy in patients with unresectable Stage III NSCLC

      Wurschmidt, F.; Garassino, M.; Faivre-Finn, Corinne; Mazieres, J.; Emeribe, U.; Franks, A.; Trunova, N.; Reck, M.; Radiologische Allianz Hamburg, Hamburg, (2020)
      Fragestellung: NSCLC macht 85 % aller Lungenkrebsfälle aus, wobei sich ~ 30 % der Patienten (Pt) im Stadium III der Erkrankung befinden. Die platinbasierte Chemoradiotherapie (CRT) war in diesem Umfeld in der Vergangenheit der SoC, dies jedoch mit schlechten Langzeitergebnissen. Durvalumab ist ein selektiver monoklonaler IgG1-Antikörper, der mit hoher Affinität die PD-L1-Bindung an PD-1 und CD80 blockiert. In der Phase-III-PACIFIC-Studie wurde Durvalumab gegenüber Placebo bei Pt mit lokal fortgeschrittenem, nicht resezierbarem NSCLC im Stadium III untersucht, die nach ≥2 überlappenden Zyklen einer gleichzeitigen CRT (cCRT) nicht progredient waren. Mit Durvalumab wurden signifikante Verbesserungen des PFS und des OS beobachtet (HR für PFS 0,52; HR für OS 0,68). Diese Daten, sowie das vergleichbare Sicherheitsprofil von Durvalumab und Placebo, definieren das PACIFIC-Regime (Durvalumab nach cCRT) als neuen SoC in diesem Setting. Ein Teil der Patienten ist jedoch aus verschiedenen Gründen nicht für eine cCRT geeignet und erhält stattdessen eine sequenzielle CRT (sCRT). PACIFIC-6 (NCT03693300) untersucht dieSicherheit, Wirksamkeit und Lebensqualität von Durvalumab bei NSCLCPatienten, die auf eine platinbasierte sCRT angesprochen haben. Methodik: PACIFIC-6 ist eine offene, multizentrische Phase-II-Studie, die in Europa und in Nordamerika durchgeführt wird. Pt mit nicht resezierbarem NSCLC im Alter von ≥ 18 Jahren mit histologisch oder zytologisch dokumentiertem Stadium III, die auf eine platinbasierte sCRT angesprochen haben und ECOG-PS ≤ 2 sind, können eingeschlossen werden. Der Einschluss ist unabhängig von Biomarkern und auf keine definierte Population beschränkt. 150 Pt erhalten 24 Mon. lang oder bis zum Fortschreiten der Erkrankung alle 4 Wo. Durvalumab (1500 mg iv). Die Pt werden nach PS-Status in 2 Kohorten unterteilt und alle 12 Wo. bewertet. Primäres Ziel ist die Bewertung der Sicherheit und Verträglichkeit von Durvalumab. Zu den sekundären Zielen zählen Wirksamkeitsparameter wie PFS, ORR, DoR sowie OS, Lungenkrebs-Mortalität und weitere Sicherheitsbewertungen. Exploratorische Ziele schließen die Bewertung von Symptomen und Lebensqualität sowie die Beurteilung des Zusammenhangs von tumorbasiertenBiomarkern mit der Wirksamkeit ein. Die Rekrutierung ist noch nicht abgeschlossen.
    • PACIFIC-6: a phase II study of durvalumab following sequential chemoradiotherapy in patients with stage III, unresectable NSCLC

      Garassino, M; Faivre-Finn, Corinne; Mazieres, J; Reck, M; Emeribe, U; Franks, A; Trunova, N; Fondazione Irccs Istituto Nazionale Dei Tumori, Milan/IT (2019)
    • PACIFIC: Overall survival with durvalumab versus placebo after chemoradiotherapy in stage III NSCLC

      Raben, D; Faivre-Finn, Corinne; Spigel, D; Daniel, D; Villegas, A; Vincente, D; Hui, R; Carpeno, J; Murakami, S; Paz-Ares, L; et al. (2018)
    • Paclitaxel plus cisplatin is as effective as regimens containing gemcitabine in people with advanced non-small cell lung cancer.

      Danson, Sarah; Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK. (2004-05)
    • Paclitaxel: a hope for advanced non-small cell lung cancer?

      Ranson, Malcolm R; Thatcher, Nick; CRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK. malcolm.ranson@man.ac.uk (1999-06)
      Recent studies have shown that paclitaxel (Taxol); Bristol-Myers Squibb Co., Princeton, NJ) is an active agent in the treatment of advanced non-small cell lung cancer (NSCLC). Early trials in patients with advanced NSCLC utilised a 24 h infusion schedule and reported objective tumour responses in 21 - 24% of patients. Shorter infusion schedules have equivalent efficacy, and combined results from 14 separate trials of single agent paclitaxel in advanced NSCLC show an overall tumour response rate of 26%. Alternative schedules of paclitaxel from the traditional regimen every three weeks are under active investigation, but it is premature to assess whether these will yield improved efficacy for patients with advanced NSCLC. A single multicentre randomised trial of paclitaxel versus best supportive care in advanced NSCLC showed a significant survival advantage for the chemotherapy arm. Two large randomised Phase III trials have shown that paclitaxel and cisplatin is modestly more effective than cisplatin and podophyllotoxin combinations. The addition of cisplatin or carboplatin to paclitaxel results in higher response rates than for each of the drugs as single agents, but it is unclear whether the combinations yield superior survival or quality of life compared to single agent paclitaxel, or to other paclitaxel-containing regimens.
    • Paediatric craniopharyngiomas: a regional review.

      Graham, P H; Gattamaneni, Rao; Birch, Jillian M; Department of Radiotherapy, Christie Hospital and Holt Radium Institute, Manchester, UK. (1992)
      Forty paediatric craniopharyngioma cases treated between 1956 and 1987 by conservative surgery (15), radical surgery (10), conservative surgery and radiotherapy (9) and shunting (6) are reviewed. The conservative surgery and radiotherapy group's local control and survival (100%) is significantly better than that of any other group. This group also achieved the most consistent level of employment or tertiary education. Overall morbidity was high. Overall survival has improved since 1976. Whether given as an adjuvant or salvage a radiotherapy dose of TDF 83 or greater gave a significantly better survival (100%) than lower doses.
    • Paediatric radiation therapy across Europe - a European questionnaire survey supported by the SIOPE, ESTRO, PROS and several national paediatric hematology-oncology societies (NAPHOS).

      Demoor-Goldschmidt, C; Carrie, C; Whitfield, Gillian A; Meijinders, P; Dieckmann, K; Banovic, P; Mekic, M; Lassen, Y; Alexopoulou, K; Giralt, J; et al. (2017)
    • A painful blistering rash on the lower legs and perineum.

      Langan, E A; Mansoor, Was; Brabant, Georg E; Jamieson, L A; Young, H S; Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester, UK (2012-04-30)
    • PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer

      Santiago-Gómez, Angélica; Kedward, T; Simoes, Bruno M; Dragoni, I; NicAmhlaoibh, R; Trivier, E; Sabin, V; Gee, J; Sims, A; Howell, Sacha J; et al. (2019)
      Despite the effectiveness of endocrine therapies to treat estrogen receptor-positive (ER+) breast tumours, two thirds of patients will eventually relapse due to de novo or acquired resistance to these agents. Cancer Stem-like Cells (CSCs), a rare cell population within the tumour, accumulate after anti-estrogen treatments and are likely to contribute to their failure. Here we studied the role of p21-activated kinase 4 (PAK4) as a promising target to overcome endocrine resistance and disease progression in ER + breast cancers. PAK4 predicts for resistance to tamoxifen and poor prognosis in 2 independent cohorts of ER + tumours. We observed that PAK4 strongly correlates with CSC activity in metastatic patient-derived samples irrespective of breast cancer subtype. However, PAK4-driven mammosphere-forming CSC activity increases alongside progression only in ER + metastatic samples. PAK4 activity increases in ER + models of acquired resistance to endocrine therapies. Targeting PAK4 with either CRT PAKi, a small molecule inhibitor of PAK4, or with specific siRNAs abrogates CSC activity/self-renewal in clinical samples and endocrine-resistant cells. Together, our findings establish that PAK4 regulates stemness during disease progression and that its inhibition reverses endocrine resistance in ER + breast cancers.
    • Palbociclib and endocrine therapy in fourth line and beyond for hormone receptor-positive HER2-negative advanced breast cancer: the UK compassionate access program experience

      Battisti, NML; Kingston, B; King, J; Denton, A; Waters, S; Sita-Lumsden, A; Rehman, F; Stavraka, C; Kristeleit, H; Sawyer, E; et al. (2019)
      Background Palbociclib is approved in 1st line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Program (CAP) previously allowed patients to receive it in 4th line. However, Palbociclib has not been specifically tested in this population. We aimed to determine the safety and efficacy profile of Palbociclib within the CAP across ten institutions in the United Kingdom. Methods We retrospectively identified HR-positive HER2-negative ABC patients on the Palbociclib CAP between December 2015 and September 2017. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher's exact test, chi-squared method and Cox regression were used as appropriate. Results 118 patients identified had median age of 59 (32-82). 97 (82.20%) were postmenopausal and 109 (92.37%) had ECOG Performance Status 0-1. 96 (81.36%) had visceral involvement, 19 (16.10%) bony only and 15 (12.71%) visceral only disease. Patients received a median 5 (range 3-11) prior lines of treatment and 3 (range 0-8) prior chemotherapy lines. 105 patients (89.74%) developed neutropenia (grade ?3 in 59 [56.19%]). 6 experienced febrile neutropenia (5.13%). 57 (48.72%) had a dose reduction, down to 100mg in 48 (41.03%) and 75mg in 9 (7.69%) due to hematologic toxicity in 46 (80.70%). Dose delays were in median 7 days long (range: 0-56). Palbociclib was discontinued due to disease progression in 97 (82.91%) and to toxicity in 5 (4.27%). Grade 3 neutropenia occurred in 45 patients (67.16%) who received ?3 and in 22 (32.84%) who received <3 prior chemotherapies (p 0.351). Palbociclib produced clinical benefit rate (CBR) of 47.52% and overall response rate of 15.84% in 101 patients assessed. CBR was 45.45% with previous endocrine treatment (ET) progression-free survival (PFS) <6 months versus 49.12% if PFS ?6 months (p 0.714). Overall, median PFS was 4.5 months (95% CI 3.7-5.9). The PFS seen in different subgroups showed no impact in relation to the number of lines of prior chemotherapy (<3 lines: 5.9 months [95% CI 3.7-11.0]; ?3 lines: 4.3 months [95% CI 3.3-5.5], p 0.159), but was numerically greater in those who had previous benefit from ET (PFS ?6 months: 5.9 months [95% CI 4.4-8.0]; <6 months: 3.7 months [95% CI 2.8-4.5], p. 0.055) or in those with bone only disease (bone only: 11.0 months [95% CI 2.3-not reached]; other sites involved: 4.4 months [95% CI 3.6-5.5], p 0.024). Median OS was 15.8 months (95% CI 13.3-18.7) for the whole cohort and it was greater in patients who derived longer PFS from prior ET (?6 months: 18.1 months [95% CI 13.0-NR]; <6 months: 14.4 months [95% CI 7.7-18.3], p. 0.052). Conclusions To date, this is the most extensive analysis of Palbociclib outcomes in ?4th-line setting. In this heavily pretreated population clinical benefit was confirmed particularly for endocrine-sensitive disease and predominantly involving the bones and in earlier lines of treatment. Grade ?3 neutropenia rates were similar to PALOMA trials, but the higher incidence of febrile neutropenia need to be carefully considered.
    • Palbociclib and endocrine therapy in heavily pretreated hormone receptor-positive HER2-negative advanced breast cancer: the UK Compassionate Access Programme experience.

      Battisti, N; Kingston, B; King, J; Denton, A; Waters, S; Sita-Lumsden, A; Rehman, F; Stavraka, C; Kristeleit, H; Sawyer, E; et al. (2019)
      PURPOSE: Palbociclib is approved in 1st line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Programme previously allowed patients to receive it in 4th line. However, Palbociclib has not been specifically tested in this population. We aimed to determine the safety and efficacy profile of Palbociclib within the Programme across ten institutions in the United Kingdom. METHODS: We retrospectively identified HR-positive HER2-negative ABC patients on the Programme between December 2015 and September 2017. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher's exact test, ?2 method and Cox regression were used. RESULTS: 118 patients identified had a median age of 59. 82.2% were postmenopausal and 92.4% performance status 0-1. 81.4% had visceral involvement and 6.8% bone-only disease after a median of 5 prior treatments and 3 prior chemotherapies. Clinical benefit rate was 47.5%, overall response rate 15.8%, median PFS 4.5 months and median OS 15.8 months. Longer progression-free survival on prior endocrine therapy was a predictor of longer PFS and OS. 89.7% developed neutropenia (grade???3 in 56.8%). 5.1% experienced febrile neutropenia. 48.3% had dose reductions and 3.4% discontinued Palbociclib following toxicity. No statistically significant difference in grade???3 neutropenia was observed according to metastatic sites nor previous treatments. CONCLUSIONS: This is the most extensive analysis of palbociclib in ??4th-line setting. Clinical benefit was confirmed particularly for endocrine-sensitive, predominantly bony disease and in earlier lines of treatment. Safety was similar to PALOMA trials with higher febrile neutropenia rate.
    • Palbociclib combined with aromatase inhibitors (AIs) in women >= 75 years with oestrogen receptor positive (ER plus ve), human epidermal growth factor receptor 2 negative (HER2-ve) advanced breast cancer: A real-world multicentre UK study

      El Badri, S.; Tahir, B.; Balachandran, K.; Bezecny, P.; Britton, Fiona; DeSouza, K.; Hills, D.; Moe, M.; Pigott, T.; Proctor, A.; et al. (2021)
      Background Breast cancer accounts for 21% of all cancer diagnoses in women aged ?75 years. The older population is under-represented in clinical trials; thus, real-world data in this patient group is critical to guide management. In this large-scale UK-wide real-world study, we evaluated the tolerability and efficacy of palbociclib combined with an AI for first-line treatment of advanced ER+ve/HER2-ve breast cancer in elderly women. Methods 14 cancer centres participated in this national retrospective study. Patients aged ?75 years who received at least one cycle of palbociclib combined with an AI for first-line treatment of advanced ER+ve/HER2-ve breast cancer were eligible. Data included baseline demographics, co-morbidities, metastatic disease burden, toxicities, dose reductions and delays, response to treatment and in-patient secondary care burden. Multivariable Cox regression was used to assess independent predictors of progression-free survival (PFS). Results 276 patients met the eligibility criteria. The median age of patients was 78 (range 75-92) years. The PFS rates at 12 and 24 months were 75.9% and 64.9%, respectively. The best radiological response was complete response (2%), partial response (32.9%) and stable disease (54.9%) with a clinical benefit rate at 24 weeks of 87%. The most common toxicities were neutropenia, fatigue, anaemia and thrombocytopenia. 50.7% of patients required a dose reduction and 59.2% required at least one dose delay. 22 patients (9.6%) required hospital admission due to toxicity and 6 patients (2.2%) had febrile neutropenia. Multivariable analysis identified fewer dose delays, increasing ECOG performance status and age-adjusted Charlson co-morbidity index, and increasing number of metastatic sites to be independent adverse predictors of PFS. Conclusions This largest known dataset of Palbociclib tolerability and efficacy in women aged ?75 years shows that this is an effective therapy that is well tolerated and appropriately managed with dose delays/reductions resulting in very low levels of clinically significant toxicity requiring hospital admission.
    • Palbociclib in combination with aromatase inhibitors in patients ≥ 75 years with oestrogen receptor-positive, human epidermal growth factor receptor 2 negative advanced breast cancer: A real-world multicentre UK study

      El Badri, S.; Tahir, B.; Balachandran, K.; Bezecny, P.; Britton, Fiona; Davies, M.; Desouza, K.; Dixon, S.; Hills, D.; Moe, M.; et al. (2021)
      Background: Breast cancer incidence increases with age and real-world data is essential to guide prescribing practices in the older population. The aim of this study was to collect large scale real-world data on tolerability and efficacy of palbociclib + AI in the first line treatment of ER+/HER2-advanced breast cancer in those aged ≥75 years. Methods: 14 cancer centres participated in this national UK retrospective study. Patients aged ≥75 years treated with palbociclib + AI in the first line setting were identified. Data included baseline demographics, disease characteristics, toxicities, dose reductions and delays, treatment response and survival data. Multivariable Cox regression was used to assess independent predictors of PFS, OS and toxicities. Results: 276 patients met the eligibility criteria. The incidence of febrile neutropenia was low (2.2%). The clinical benefit rate was 87%. 50.7% of patients had dose reductions and 59.3% had dose delays. The 12- and 24- month PFS rates were 75.9% and 64.9%, respectively. The 12- and 24- month OS rates were 85.1% and 74.0%, respectively. Multivariable analysis identified PS, Age-adjusted Charlson Comorbidity Index (ACCI) and number of metastatic sites to be independent predictors of PFS. Dose reductions and delays were not associated with adverse survival outcomes. Baseline ACCI was an independent predictor of development and severity of neutropenia. Conclusion: Palbociclib is an effective therapy in the real-world older population and is well-tolerated with low levels of clinically significant toxicities. The use of geriatric and frailty assessments can help guide decision making in these patients.