Bidirectional receptor crosstalk in breast cancer: the role of c-myc and coregulatory proteins and future implications for cancer treatment.

Background Progression of breast cancer despite hormonal and biological treatments continues to pose a therapeutic challenge. Receptor crosstalk is a resistant mechanism that can occur between the estrogen receptor (ER) and the receptor tyrosine kinases, such as HER2, in response to inhibition by anti-endocrine treatments. Briefly, tumours can overactivate growth factor signalling cascades and give rise to an endocrine independent tumour. Wehypothesized that treatment with tyrosine kinase receptor inhibitors (TKIs), trastuzumab (Herceptin®) and lapatinib (Tyverb®), could induce similar receptor crosstalk by overactivating endocrine-driven tumour growth. Methods Proteomic analysis (LC-Mass Spectrometry) was used to assess proteins that interact with the proto-oncogene, c-Myc, that are involved in growth factor driven tumorigenesis and invasion. We compared c-Myc associated proteins in the ER-overexpressing MCF7 cell line and the ER and HER2-positive, endocrine-independent LCCl cells. With our findings, we proceeded to better elucidate the function and importance of these interactions both in vitro and by analysis of our clinical breast cancer patient cohort. Finally, we utilized protein macroarray technology to uncover autoantibodies in HER2-positive breast cancer patients that could potentially serve as biomarkers to idenbfy patients developing tumour resistance to trastuzumab, as well as other roles. Results LC- Mass Spectrometry revealed a novel interaction between the proto-oncogene c-Myc and the corepressor, SMRT in endocrine sensitive MCF7 cell line, but not in the LCCl cell line. We hypothesized that SMRT may be silencing the oncogenic effects of c-Myc in the endocrine dependent tumour model. Coirnmunoprecipitation revealed this interaction was lost when cells were treated with TKIs, thus liberating c-Myc from SMRT repression and enhancing c-Myc transcriptional activity as reflected by increased expression of the downstream target gene, survivin. Furthermore, the endocrine pathway became overactive with recruitment of the coactivator, CBP to ERα and increased levels of PS2 reflecting ER activity. Clinically, in our HER2-overexpressingearly, node-negative breast cancer patient population who received trastuzumab, thosewho also overexpressed ER were noted to have an increased risk of recurrence (18% vs10%). When anti-estrogen treatments were used in combination with TKI treatments, a number of in vitro observations were made. The dual treatment had a superior inhibitory effect upon cell growth, c-Myc recruited SMRT once again silencing its transcriptional ability and CBP / ERα interaction was reduced. PEX protein macroarray comparative analysis of HER2-positive and HER-negative patients revealed a list of autoantibodies that can be detected in patient sera. These may be of benefit as biomarkers in the future management of breast cancer patients. The ER coactivator, Ada3, detected in HER2-overexpressing patient sera did not associated with the larger patient group and is unlikely to be useful as a marker of receptor crosstalk or tumour recurrence. Further work on the other identified autoantibodies may uncover more promising proteins. Conclusion This work reveals the possibility of bidirectional receptor crosstalk between the growth factor and endocrine pathways in breast cancer. It also suggests a role for the protooncogene, c-Myc and the coregulatory proteins, SMRT and CBP in this relationship. This has clear implications for the future treatment of breast cancer and indicated thatpatients, who overexpress ER and HER2, may require simultaneous treatment regimes with anti-estrogen and anti-growth factor therapies. It also raises the pressing need to identify the tumours that are more likely to progress despite TKI therapy by discovering biomarkers that can aid clinical and radiological investigations

Tisotumab Vedotin in Combination with Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer:Results from the innovaTV 205/GOG-3024/ENGOT-cx8 Study

PURPOSE Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E).CONCLUSION TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.</p

Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial

Background Tisotumab vedotin is a first-in-human antibody–drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor. Methods InnovaTV 201 is a phase 1–2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ≥18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0–1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing. Findings Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2–22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment. Interpretations Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours

Current Irish medicolegal landscape: an unsustainable trajectory

A number of outstanding clinical claims that are yet to be resolved as well as their associated estimated costs are at a record high in Ireland. By the end of 2022, the Irish government face 3875 active clinical claims which are expected to cost €3.85 billion in total. This does not account for future claims yet to be brought. The financial burden will be borne by the Irish healthcare system which is already facing unprecedented pressures on its services and staff. If current trends continue, the opportunity costs of the current medicolegal landscape will impact the future provision of healthcare. Aside from the financial consequences, clinical claims have numerous negative impacts on all parties involved. Gaining an understanding as to why claims and costs continue to increase relies on access to, and analysis of high-quality patient safety data, including learning from previous litigation. Addressing the causal and perpetuating factors requires efficient implementation of evidence-based recommendations through engagement with stakeholders, including the public. It is necessary to continuously assess the implementation of recommendations as well as measure their impact. This is to ensure that novel efforts from this point onwards do not suffer the same fate as many previous recommendations that, because of a lack of follow-on research, appear to go no further than the page of the report they are written. Action is required now to change the course of the currently unsustainable trajectory of the Irish medicolegal landscape

National incidence, management and survival of urachal carcinoma

Urachal carcinoma is an uncommon cancer whose rarity has precluded its study and evidence-based management strategies are lacking. This study assessed all urachal carcinomas in Ireland and clinical parameters in order to improve understanding. Urachal carcinomas diagnosed from 1994 to 2011 were identified from the National Cancer Registry in Ireland. Data obtained included patient age, gender, diagnostic year, pathology, tumor stage, patient treatment strategies and survival. Twenty-six urachal carcinomas were identified, the majority being adenocarcinoma. This comprised 0.3% of all invasive bladder tumors. Patients were predominantly male (62%) and over 50 years of age (58%). Twenty-two patients (85%) underwent surgery, with only six (23%) undergoing chemotherapy. On average, median overall survival was 2.6 years (range 0-15.2 yrs). Survival was longer in women (5 vs. 1.9 yrs), patients under 50 years of age (3.6 vs. 1.9 yrs), those without confirmed metastasis (4.1 vs. 0.7 yrs) and those who received chemotherapy (3.6 vs. 2.6 yrs). The overall survival of urachal carcinoma in Ireland is less than expected from published literature. This study highlights the need for centralization of rare tumors with international collaboration to identify the optimal treatment strategy and improve outcome

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA–MONO/GOG-3020/ENGOT-ov45)

PURPOSE: ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA-MONO comparison of rucaparib versus placebo. METHODS: Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population. RESULTS: As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P =.0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P <.0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%). CONCLUSION: Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45)

PURPOSEATHENA (ClinicalTrials.gov identifier: ) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA-MONO comparison of rucaparib versus placebo.METHODSPatients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population.RESULTSAs of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P &amp;lt; .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade &amp; GE; 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%).CONCLUSIONRucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.Funding Agencies|Clovis Oncology Inc.; NIHR Cambridge Biomedical Research Centre; [BRC-1215-20,014]</p