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  • American Association for Cancer Research (AACR)  (11)
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  • 1
    Online Resource
    Online Resource
    Abstract P3-06-01: Clonal evolution and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P3-06-01-P3-06-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P3-06-01-P3-06-01
    Abstract: Background: Understanding to what extent a breast tumor's genetic composition may change over the course of a few months of neoadjuvant therapy has implications for optimal therapeutic approach. However, genomic changes observed across treatment may result from either treatment-induced clonal evolution or geographically disparate sampling of a heterogeneous tumor. We sought to characterize the geographic heterogeneity in primary breast tumors, and to incorporate this information into analysis of clonal evolution with neoadjuvant therapy. Methods: We assembled the largest cohort to date of multi-region (n=2-3) whole-exome sequenced (WES) or whole-genome sequenced untreated primary breast tumors with matched normal and adequate tumor purity for analysis: four tumors with data generated for this study and five tumors compiled from three previous studies. We also generated the first cohort of multi-region (n=2-6) WES breast tumors post-neoadjuvant HER2-targeted therapy and chemotherapy, sequencing one region from a pre-treatment diagnostic specimen, multiple regions from the post-treatment surgical specimen, and matched normal for five HER2+ breast tumors that did not achieve a pathologic complete response. We used an agent-based model of spatial tumor growth to investigate whether the mutational patterns we observed with treatment were consistent with pre-existing heterogeneity or treatment-induced selection. Results: In untreated primary breast tumors, on average 30% (range 1-70%) of apparently clonal mutations from a single region were absent or rare in a second, spatially disparate region (high-frequency regional, or HFR). Intra-tumor heterogeneity was similar post-treatment (HFR 28%, range 10-54%), and was higher in breast tumors than in previously analyzed colon, brain, lung, and esophageal tumors. Simulation studies confirmed that with high heterogeneity as observed in breast tumors, analysis of one pre-treatment and one post-treatment region could not distinguish treatment-induced clonal evolution from pre-existing heterogeneity; however, obtaining at least two post-treatment regions allowed for detection of clonal shifts with treatment. Analysis of multi-region data revealed that clonal replacement occurred with neoadjuvant therapy in two of the five tumors. Candidate causes of therapeutic resistance included amplifications in CCND1, ERBB4, and MYC in one subclone, and functional protein-altering mutations in ERCC2, SMO, and WT1 in another. Mathematical modeling suggested that these putative resistant subclones comprised 0.02-12.5% of the overall pre-treatment cell population, substantially larger than previous estimates of resistant tumor clone size. Conclusions: WES data from multiple regions of untreated and treated primary breast tumors revealed considerable heterogeneity that remained present throughout treatment with chemotherapy and HER2-targeted therapy, even while major clonal sweeps took place in a minority of tumors. Obtaining at least two samples for analysis from breast tumors post-neoadjuvant therapy may reveal the tumor's evolutionary path and, especially as increasing numbers of molecular and immune therapeutic targets are identified, inform new clinical strategies. Citation Format: Caswell-Jin JL, McNamara K, Reiter JG, Sun R, Hu Z, Ma Z, Suarez CJ, Tilk S, Raghavendra A, Forte V, Chin S-F, Bardwell H, Provenzano E, Caldas C, Lang J, West R, Tripathy D, Press MF, Curtis C. Clonal evolution and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P3-06-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
    Online Resource
    Online Resource
    Abstract B05: Assessing and removing biophysical barriers to treatment
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 13_Supplement ( 2015-07-01), p. B05-B05
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 13_Supplement ( 2015-07-01), p. B05-B05
    Abstract: Pancreatic ductal adenocarcinoma (PDA) is a confounding cancer with a penchant for metastasis and resistance to therapy. Cell autonomous events, such as mutations in the Kras proto-oncogene, are essential for the initiation and maintenance of PDA; however non-malignant cells as well as non-cellular components have been shown to contribute to tumor growth, immunosuppression, and chemotherapeutic resistance. The stromal compartment can comprise more than 80% of tumor content and is characterized by a dynamic and deregulated extracellular matrix (ECM). In addition to a role in tissue structure, the ECM provides biophysical and biochemical cues that determine cell responses. PDA presents its own characteristic ECM signature including large deposits of the negatively charged glycosaminoglycan (GAG) hyaluronan (HA), as well as fibrillary collagens which increases matrix stiffness. We have previously demonstrated that high levels of HA in PDA contribute to extraordinary interstitial fluid pressures (IFP) and vascular collapse. We show here that IFP is comprised of both freely mobile and immobile fluid phases. Due to its highly charged nature, HA binds large amounts of water to create an immobile-fluid phase with a significant swelling pressure. This pressure is not detected by conventional methods that can measure only free fluid pressure. The swelling pressure stresses abundant collagen fibrils which contract through cellular efforts to maintain homeostasis, further contributing to IFP. Targeting HA through systemic administration of pegylated hyaluronidase (PEGPH20) liberates the immobile fluid phase and dramatically reduces IFP, increasing vessel patency and bioavailability of systemically delivered agents. We present results on the effects of targeting additional ECM components and signaling pathways to help remove biophysical barriers to chemotherapeutic access. We also compare the abilities of different methodologies to measure interstitial pressures associated with the distinct fluid phases in a variety of experimental contexts. Citation Format: Kathleen E. DelGiorno, Markus Carlson, Paolo P. Provenzano, Scott Brockenbough, Sunil R. Hingorani. Assessing and removing biophysical barriers to treatment. [abstract] . In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B05.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA2014-B05
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
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    Online Resource
    Abstract OT3-04-03: PARTNER randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 4_Supplement ( 2018-02-15), p. OT3-04-03-OT3-04-03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 4_Supplement ( 2018-02-15), p. OT3-04-03-OT3-04-03
    Abstract: Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC subgroup show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Trial design: 3 stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Methods: Stage 1 Safety: both research arms combined. Stage 2 Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pickthewinner” design with 53 patients in each research arm. This allows a 90% power, 5% onesided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3 Efficacy:anticipated pCR ˜55-60% for all trial patients and ˜60-65% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure required gBRCA patients are enrolled. Enrichment design is applied with overall significance level 0.05(α) = 0.025(αall)+ 0.025(αgBRCA) and 80% power. Target accrual: 527 [gBRCA 220] Current accrual: 56 Sites activated: 15 [expected number of sites 30-50] . Citation Format: Abraham J, Vallier A-L, Qian W, Grybowicz L, Thomas S, Machin A, Harvey C, Chiu E, McAdam K, Hughes-Davies L, Roylance R, Copson E, Armstrong A, Provenzano E, Tischkowitz M, McMurtry E, Earl H. PARTNER randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-04-03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS17-OT3-04-03
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 4
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    Online Resource
    Sentinel lymph node biopsy (SLNB) prior to primary chemotherapy (PC) in breast cancer patients.
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 2_Supplement ( 2009-01-15), p. 5111-
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 2_Supplement ( 2009-01-15), p. 5111-
    Abstract: Abstract #5111 Background: Lymph node status is the single most important determinant of prognosis and is used for planning adjuvant therapy. Patient selection and timing of SLNB for PC continue to evolve; SLNB prior to PC may allow more accurate initial staging and prognostication and guide decisions about adjuvant treatment. & #x2028; Methods: 78 patients (pts) who were treated in the Cambridge Breast Unit as part of Neo-tAnGo (a multicentre PC trial). 57 were identified as potentially suitable for SLNB pre-PC (clinically node negative, non-inflammatory tumours 2–5cm in size). 38 had axillary ultrasound, and of these, 18 had sonographically suspicious nodes. 12/18 had confirmed nodal metastasis on core biopsy (CB) and had direct ALND post-PC. The remaining 20 patients had innocent nodes or were CB negative, of whom 19 underwent SLNB. A total of 19 patients in this subgroup did not undergo axillary ultrasound; 16 of these proceeded to ALND post-PC and 3 to SLN biopsy pre-PC according to unit policy at the time. A total of 22 (19 + 3) pts were available for analysis of SLN biopsy pre-PC in terms of time to treatment compared to the remainder of the centre's cohort in the Neo-tAnGo study. 42, (22 SLNB + 20 node positive on CB), were analysed as having axillary pathological staging before PC and compared to the other patient cohort on study. & #x2028; Results: The SLN was successfully identified in all 22 pts using dual localisation techniques with a mean SLN harvest of 2.8 nodes per patient (range 1–10). 6/22 pts (27%) were node positive, and 5 had single SLN involvement (4 macro-; 1 micro-) and one had a macro- and a micrometastasis in 2 different nodes. The mean time from diagnosis to start of PC in the SLN group was 23 days (range 8–43) compared 18 days (range 7–36) for the comparator cohort on study (p=0.02). When all 42 pts with pathological axillary assessment were analysed (including clinically node positive pts with tumours & gt;5cm), there was no significant difference in time from diagnosis to start of PC for pts undergoing CB and/or SLNB (21 days) compared with no axillary assessment (17 days) (wilcoxon test p=0.10). The mean number of nodes removed on completion ALND was 9 (range 4–16). There was no evidence of any viable tumour or fibrosis in any of the non-SLN's (NSLN) examined. Amongst the group of 18 ultrasound/CB positive pts who underwent ALND without SLNB, nodal disease was found in 9 (50%) with evidence of pathological downstaging in 4 (22%). & #x2028; Conclusion: There is potential loss of staging information when SLNB is performed after PC and the clinical significance of a negative SLNB result in this setting is uncertain. A combination of axillary ultrasound (with CB) and SLNB can more accurately stage the axilla without significant overall delays in commencement of PC for clinically node positive and negative pts. Downstaging of disease in NLSN may occur in response to PC with a lower NSLN rate (0%) when compared to primary surgical treatment in smaller tumours (15–25%). Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5111.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS-5111
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 5
    Online Resource
    Online Resource
    Abstract 1487: Modulation of pancreas cancer invasion and metastasis by SMAD4/DPC4 signaling
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1487-1487
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1487-1487
    Abstract: Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal disease with the highest 1 and 5 year mortalities of any cancer. PDA is notoriously difficult to detect and resistant to all current therapeutic modalities. Moreover, most patients present at diagnosis with locally advanced or frankly metastatic disease; median survival in this setting is approximately 6 months. For the few patients ( & lt;15%) for whom surgical resection is possible, median survival increases to 2 years but is not durable: survival at 5 years is only 20% and continues to decline to less than 2% at 10 years. Tellingly, the majority of these patients also eventually die of metastatic disease suggesting that clinical stage I tumors are, in fact, already micrometastatic stage IV. Thus, understanding the mechanisms underlying this unusual drive for metastasis is essential to developing therapies that meaningfully prolong survival in pancreas cancer patients. A dearth of tissue specimens from primary pancreas cancers and, especially, from metastatic lesions, has hindered scientific study of this disease. Nevertheless, knowledge gleaned from studies of these scarce resected tissues has generated testable hypotheses and guided recent successful efforts to faithfully model the disease in mice. We and others have systematically engineered key oncogene and tumor suppressor gene (TSG) mutations into endogenous murine loci revealing critical insights into disease pathogenesis. We now know, for example, that activating mutations in the Kras proto-oncogene initiate preinvasive disease and that the resultant pancreatic intraepithelial neoplasms (PanIN) progress spontaneously to invasive and metastatic PDA. Disease progression can be hastened in the context of concomitant mutation of Trp53 or p16/p19. Interestingly, heterozygous mutation of Smad4/Dpc4 in the context of oncogenic Kras alters the differentiation state of the precursor lesions to instead generate mucinous cystic neoplasms (MCN). These lesions progress more slowly, and with a lower metastatic burden, to invasive PDA through a combination of LOH of Dpc4 and mutation of either Trp53 or p16. Thus, the relative timing of mutations in these TSG contributes to determining the pathobiology and prognosis of the resulting disease. We have further explored the effects of Dpc4 mutation on disease behavior by generating KrasLSL-G12D/+;Trp53LSL-R172H/+;Dpc4flox/+;Cre (KPDC) animals. Somewhat surprisingly, these animals display the same median survival as KrasLSL-G12D/+;Trp53LSL-R172H/+;Cre (KPC) mice, albeit with a different spectrum of metastatic spread. Through a combination of in vivo and in vitro analyses, we have revealed critical pathways that serve to modulate the relative balance in PDA cells between proliferation, differentiation, invasion and metastasis. These studies identify specific targets to pursue therapeutically for distinct stages of disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1487. doi:10.1158/1538-7445.AM2011-1487
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-1487
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 6
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    Abstract OT2-24-01: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. OT2-24-01-OT2-24-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. OT2-24-01-OT2-24-01
    Abstract: Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive subgroup lacking targeted therapy. Germline BRCA (gBRCA) breast cancer and TNBC share some phenotypic and molecular similarities, with 10%-20% of TNBC patients having gBRCA mutations. Homologous recombination deficient tumours are particularly sensitive to PARP inhibitors such as olaparib (Lynparza). It has been shown that adjuvant olaparib for patients with high-risk, HER2-negative early breast cancer and gBRCA pathogenic or likely pathogenic variants after adjuvant or neoadjuvant chemotherapy significantly improves 3-year invasive and distant disease-free survival compared to placebo (OlympiA). Aim: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR) rate). Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Randomisation (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. This trial includes an optional pathway (PARTNERING) aiming to establish if the addition of new agents (ATR inhibitor and PDL1 inhibitor) can improve response in those patients with evidence of residual disease before surgery. Eligibility criteria: Aged 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; clinical stage T1-4 N0-2; performance status 0-1; treatment commenced within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. Statistical methods: The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients and the TNBC non-gBRCA cohort) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy. It is planned to recruit a minimum of 188 gBRCA patients. A maximum of 15 patients will be allocated into each PARTNERING cohort. Present accrual: Recruitment commenced 27 May 2016 and 678 patients from 30 sites have been accrued to date. The IDSMC reviewed the trial after Stages 1 and 2 and recommended to continue the trial without change. Data analysis for Stage 2 revealed no safety concerns and research arm 2 (olaparib on day 3 to day 14) was selected. Stage 3 Phase I recruitment is in progress (recruiting TNBC non-gBRCA and gBRCA patients) and we anticipate moving to Phase II (recruiting gBRCA patients only) by early 2022. Four patients have been accrued to the PARTNERING optional pathway to date. The trial is open and enrolling patients to UK and international sites. Contact information: partner@addenbrookes.nhs.uk Citation Format: Lynsey M Drewett, Karen A Pinilla, Louise Grybowicz, Jerome Wulff, Alimu Dayimu, Nikolaos Demiris, Jessica Martin, Camila Maida de Pontes, Nicola Johnson, Caron Harvey, Erdem Demir, Kimberley St John Green, James Jones, Gemma Young, Anne-Laure Vallier, Wendi Qian, Andrea Machin, Karen McAdam, Rebecca Roylance, Ellen R Copson, Anne Armstrong, Nicola Levitt, Elena Provenzano, Marc Tischkowitz, Emma McMurtry, Helena Earl, Jean E Abraham. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-24-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-OT2-24-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 7
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    Abstract OT2-01-15: PARTNER - Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 4_Supplement ( 2017-02-15), p. OT2-01-15-OT2-01-15
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 4_Supplement ( 2017-02-15), p. OT2-01-15-OT2-01-15
    Abstract: Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive sub-group. Early effective treatment can lead to cure. Current standard treatment is systemic chemotherapy either pre-/post-definitive surgery. No specific targeted therapies are available for TNBC. There are phenotypic and molecular similarities between germline BRCA (gBRCA) breast cancer and TNBC. In TNBC 10%-20% harbour gBRCA mutations. In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways allow drugs called PARP inhibitors (olaparib) to work particularly effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for TNBC and/or gBRCA breast cancer is safe and improves efficacy. Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant olaparib +/- platinum containing chemotherapy followed by clinicians' choice of anthracycline regimen. Stage 1 and 2, patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 chemotherapy - 4 cycles) or one of two research arms which uses the same chemotherapy regimen but with two different schedules of olaparib 150mg BD). Stage 3: patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Primary outcome measures: Stage 1: safety of the addition of olaparib to chemotherapy. Prophylactic G-CSF is mandatory. Stage 2: pathological complete response (pCR) in each of the two research arms. At the end of stage 2, one of the research arms will be dropped. Stage 3: pCR at surgery after neoadjuvant treatment. pCR - defined as no residual invasive carcinoma within the breast (ductal carcinoma in situ permitted) AND no evidence of metastatic disease within the lymph nodes. Eligibility: •Aged 16 to 70. •Written informed consent. •Histologically confirmed invasive breast cancer. •Clinical stage T1-4 N0-2 (tumour or metastatic node diameter & gt;10mm) •Confirmed ER-negative and HER2-negative or gBRCA mutation positive, irrespective of hormone status. •Performance Status 0-1 Statistical Methods: Stage 1, Safety: both research arms combined. Stage 2, Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pick-the winner” design with 53 patients in each research arm. This allows a 90% power, 5% one-sided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3, Efficacy: anticipated pCR ∼45-55% for all trial patients and ∼50-60% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure the required number of gBRCA patients are enrolled. Enrichment design is applied with the overall significance level 0.05(α)=0.025(αall)+ 0.025(αgBRCA) and 80% power. Present accrual: 1 [Trial opened: 23rd May 2016] Target accrual: 527 (TNBC 307; gBRCA 220) Contact information: Dr. Jean Abraham; Email: ja344@medschl.cam.ac.uk. Citation Format: Abraham JE, Vallier A-L, Qian W, Grybowicz L, Thomas S, Mahmud S, Harvey C, McAdam K, Hughes-Davies L, Roylance R, Copson E, Brown J, Provenzano E, Tischkowitz M, Earl HM. PARTNER - Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-15.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS16-OT2-01-15
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 8
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    Abstract OT3-03-03: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. OT3-03-03-OT3-03-03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. OT3-03-03-OT3-03-03
    Abstract: Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group share some phenotypic and molecular similarities with germline BRCA (gBRCA) tumours. In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (Olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Methods: Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A total of 527 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy. Trial Progress: PARTNER has been recruiting in UK since 27th May 2016. IDSMC recommended to continue the trial without change after reviewing the Stage 1 safety data. The recruitment of stage 2 was completed in April 2018 and results to be reviewed by the IDSMC in early 2019. The trial is open and enrolling patients to national and international sites. Citation Format: Abraham J, Vallier A-L, Qian W, Machin A, Grybowicz L, Thomas S, Weiss M, Harvey C, McAdam K, Hughes-Davies L, Roberts A, Roylance R, Copson E, Pinilla K, Armstrong A, Provenzano E, Tischkowitz M, McMurty E, Earl H. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-03-03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-OT3-03-03
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 9
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    Abstract OT3-01-02: PARTNERING / PARTNER : Phase II sub-study to establish if the addition of combinations of new agents (olaparib, cell cycle and immune checkpoint inhibitors) can improve the rate of pathological complete response (pCR) and minimal residual disease (MRD) in triple negative breast cancer (TNBC) and / or germline BRCA mutated (gBRCAm) patients with evidence of residual disease after PARTNER therapy
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. OT3-01-02-OT3-01-02
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. OT3-01-02-OT3-01-02
    Abstract: Background: In patients with TNBC, following standard neoadjuvant chemotherapy, residual disease (RD) is correlated with poor prognosis and 50% relapse within 5 years [1]. PARTNER is a neoadjuvant clinical trial which randomises TNBC and gBRCAm patients to carboplatin and paclitaxel +/- olaparib followed by anthracycline-based chemotherapy. Patients with RD after neoadjuvant treatment in this trial also face poorer survival outcomes, due to the paucity of treatment options. PARTNERING, develops a new strategy using novel agent combinations as an alternative pathway for patients with RD within the PARTNER trial. Methods: PARTNERING is a phase II open label, sub-study with a two-stage Simon design with biomarker guided treatment cohorts open only to patients in the PARTNER trial. A maximum of 15 patients will be included in each cohort. Patients with RD & gt; 10% tumour cellularity (TC) on biopsy after neoadjuvant therapy will be eligible. Patients who have no tumour cells or & lt; 10% TC, and those with progressive disease will be excluded. Allocation of patients into the cohorts will be based on tumour infiltrating lymphocytes (TILs) expression either on diagnostic or post treatment biopsy. Patients with tumours with TILs score ≤20% are considered “non-immunogenic” They will be stratified according to HRD status and allocated to receive a cell cycle checkpoint inhibitor + olaparib. Patients with a TILs score & gt;20% are considered “immunogenic” and will be allocated to receive an immune checkpoint inhibitor with olaparib or a cell cycle checkpoint inhibitor. Primary outcome measure is pCR / MRD rate at surgery after the administration of 2 cycles / 8 weeks of a combination of new agents. The rate of conversion to pCR/MRD will be correlated with TC, TILs, BRCA and homologous recombination deficiency (HRD) status, Ki67% and previous olaparib treatment. Progress: The PARTNERING pathway in the PARTNER trial will be open late 2018. Citation Format: Abraham JE, Vallier A-L, Qian W, Machin A, Grybowicz L, Thomas S, Weiss M, Harvey C, McAdam K, Hughes-Davies L, Roberts A, Provenzano E, Pinilla K, Roylance R, Copson E, Armstrong A, McMurtry E, Tischkowitz M, Earl HM. PARTNERING / PARTNER : Phase II sub-study to establish if the addition of combinations of new agents (olaparib, cell cycle and immune checkpoint inhibitors) can improve the rate of pathological complete response (pCR) and minimal residual disease (MRD) in triple negative breast cancer (TNBC) and / or germline BRCA mutated (gBRCAm) patients with evidence of residual disease after PARTNER therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-01-02.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-OT3-01-02
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
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    Abstract CT562: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of Olaparib to Platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT562-CT562
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT562-CT562
    Abstract: Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive subgroup lacking targeted therapy. TNBC and Germline BRCA (gBRCA) breast cancer share certain phenotypic and molecular similarities, with gBRCA mutations seen in 10% to 20% of TNBC patients. Homologous recombination deficient tumours, especially those caused by germline or somatic BRCA mutations, are thought to be particularly sensitive to PARP inhibitors. Aim: To establish if the addition of Olaparib to neoadjuvant Platinum-based chemotherapy in the treatment of basal TNBC and/or gBRCA breast cancer is safe and increases efficacy. Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant Paclitaxel and Carboplatin +/- Olaparib, followed by clinicians' choice of Anthracycline regimen. Stages 1 and 2: Randomisation (1:1:1) to control (3-weekly carboplatin AUC5/weekly with paclitaxel 80mg/m2 for 4 cycles), or to one of two research arms. These use an identical chemotherapy regimen and also include different treatment schedules of Olaparib 150mg BD for 12 days. Stage 3: Randomisation (1:1) to either the control or research arm chosen following stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection based on pCR rate and Olaparib completion rate using a “pick-the-winner” design. Stage 3: pCR rate. This trial includes an optional pathway (PARTNERING) for patients with evidence of residual disease after six chemotherapy cycles. This aims to establish if the addition of new agents (ATR inhibitor and PD-L1 inhibitor) improves treatment response. Eligibility criteria: Aged 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; stage T1-4 N0-2; performance status 0-1; treatment within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. Statistical methods: The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients and TNBC non-gBRCA cohort) and 20% (gBRCA patients) by combining Olaparib with Platinum based chemotherapy. A minimum of 478 TNBC non-gBRCA and 188 gBRCA patients will be recruited. Each PARTNERING cohort will consist of 15 patients. Current Enrollment: Since May 2016, 756 patients from 30 sites have been enrolled. Stages 1 and 2 are completed. An IDSMC review identified no safety concerns and Research Arm 2 was selected. This arm involves Olaparib administration on days 3-14. Stage 3 Phase I (recruitment of non-gBRCA and gBRCA patients) completed in December 2021. Stage 3 Phase II (recruitment of gBRCA patients only) remains open to patients to UK and internationally. 5 patients have been enrolled in PARTNERING. ClinicalTrials.gov Identifier: NCT03150576 Citation Format: Lynsey Drewett, Karen A. Pinilla, Louise Grybowicz, Jerome Wulff, Alimu Dayimu, Nikolaos Demiris, Rebecca Lucey, Anne-Laure Vallier, Wendi Qian, Andrea Machin, PARTNER Research Team, Karen McAdam, Rebecca Roylance, Ellen R. Copson, Anne Armstrong, Nicola Levitt, Elena Provenzano, Marc Tischkowitz, Emma McMurtry, Helena Earl, Jean E. Abraham. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of Olaparib to Platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT562.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-CT562
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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