WNT5A is a putative epi-driver of prostate cancer metastasis to the bone.

BACKGROUND: Current diagnostic tools are unable to distinguish low-grade indolent prostate cancer (PrCa) from that with a propensity to become metastatic and/or lethal. Recent evidence suggests that reprogramming of the transcriptome may drive the metastatic phenotype, and that this reprogramming is controlled, at least in part, by epigenetic changes to the DNA of cancer cells, including methylation. These changes, referred to as 'epigenetic drivers,' have previously been associated with cancer cell survival. METHODS: Here, using Illumina Methylation EPIC array data of paired primary PrCa and metastatic bone samples, we identified WNT5A as a putative epi-driver of PrCa metastasis to the bone, which was further validated in vitro. RESULTS: Significantly higher WNT5A methylation was observed in primary PrCa samples and 22Rv1 cells compared to metastatic bone samples and PC-3 cells. This higher methylation was associated with significantly lower WNT5A gene expression. CONCLUSION: Given the limited effective therapies available for metastatic cancer sufferers, particularly those whose disease has metastasised to the bone, WNT5A presents as a potential putative target for therapy.

Comparison of Echocardiography and Multi-Planar Gated Acquisition Scans for Predicting Cancer-Treatment-Related Cardiovascular Dysfunction.

BACKGROUND: Current guidelines recommend using sequential cardiac imaging to monitor for cancer treatment-related cardiac dysfunction (CTRCD) in patients undergoing potentially cardiotoxic chemotherapy. Multiple different imaging cardiac modalities are available and there are few prospective head-to-head comparative studies to help guide treatment. OBJECTIVES: To perform an exploratory prospective cohort study of "real-world" CTRCD comparing multigated acquisition nuclear ventriculography (MUGA) at the referring cancer specialist's discretion with a novel echocardiographic strategy at an Australian tertiary hospital. METHOD: Patients were recruited from haematology and oncology outpatient clinics if they were scheduled for treatment with anthracyclines and/or trastuzumab. Patients underwent simultaneous MUGA-based cardiac imaging (conventional strategy) at a frequency according to evidenced-based guidelines in addition to researcher-conducted echocardiographic imaging. The echocardiographic imaging was performed in all patients at time points recommended by international society guidelines. Outcomes included adherence to guideline recommendations, concordance between MUGA and echocardiographic left ventricular ejection fraction (LVEF) measurements, and detection of cardiac dysfunction (defined as >5% LVEF decrement from baseline by three-dimensional [3D]-LVEF). A secondary end point was accuracy of global longitudinal strain in predicting cardiac dysfunction. RESULTS: In total, 35 patients were recruited, including 15 with breast cancer, 19 with haematological malignancy, and one with gastric cancer. MUGA and echocardiographic LVEF measurements correlated poorly with limits of agreement of 30% between 3D-LVEF and MUGA-LVEF and 37% for 3D-LVEF and MUGA-LVEF. Only one case (2.9%) of CTRCD was diagnosed by MUGA, compared with 12 (34.2%) cases by echocardiography. Four (4) patients had >10% decrement in 3D-LVEF that was not detected by MUGA. Global longitudinal strain at 2 months displayed significant ability to predict CTRCD (area under the curve, 0.75, 95% confidence interval, 0.55-0.94). CONCLUSIONS: The MUGA correlates poorly with echocardiographic assessment with substantial discrepancy between MUGA and echocardiography in CTRCD diagnosis. Echocardiographic and MUGA imaging strategies should not be considered equivalent for imaging cancer patients, and a single imaging modality should ideally be used per patient to prevent misdiagnosis by inter-modality variation These findings should be considered hypothesis-generating and require confirmation with larger studies.

A tailored approach to horizon scanning for cancer medicines.

BACKGROUND: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement. METHOD: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type. RESULTS: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation. CONCLUSION: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective. POLICY SUMMARY: Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities.

Advanced fumarate hydratase-deficient renal cell carcinoma responding to combination immune checkpoint inhibitors.

Fumarate hydratase deficient (FHdef) renal cell carcinoma (RCC) is rare, highly aggressive and is believed to arise mostly in the setting of hereditary leiomyomatosis RCC (HLRCC) syndrome with a germline mutation of fumarate hydratase (FH) gene. There is currently little evidence regarding the most effective systemic treatment for advanced FHdef RCC. We present three cases of metastatic FHdef RCC, all achieving tumor response with combination immunotherapy ipilimumab and nivolumab (Ipi/Nivo). A 50-year-old male, a 27-year-old male and a 48-year-old female. The clinical features, diagnosis and medical imaging are reviewed.

Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy.

Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also show that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorises patients into four immune clusters correlated with survival. The immune suppressed cluster is associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster is associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5, CD8A, and NKG7. The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials.

Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2 + /HR + metastatic breast cancer.

PURPOSE: Dual anti-HER2 targeted therapy and chemotherapy is the current first-line standard of care for HER2 + metastatic breast cancer (MBC), with endocrine therapy (ET) the backbone of treatment in hormone receptor positive (HR +) disease. The potential ET benefit in HER2 + /HR + patients is unknown as pivotal dual anti-HER2 clinical trials precluded ET use. METHODS: Real-world data from a multi-site registry of consecutive HER2 + MBC patients treated at clinician discretion were examined. Patients that were HR + (ER + and/or PR +) and had received first-line chemotherapy alongside trastuzumab and pertuzumab were explored. Of 362 patients in the registry, 215 were excluded due to being HR- (n = 210) or not receiving chemotherapy (n = 5). RESULTS: Of the 147 patients included, 91 (62%) received concurrent ET and 56 (38%) had not. Comparing the groups, there were no significant differences in age, performance status, metastatic sites, use of previous therapy and de novo metastatic disease. More patients with ER + PR + disease versus those with ER + PR- or ER-PR + received ET (73 vs 45%). The addition of ET was associated with significantly improved 5-year PFS (HR 0.58, CI 0.37-0.89, p = 0.014) and OS (HR 0.52, CI 0.31-0.90, p = 0.018), with no increase in adverse events noted. CONCLUSION: The addition of ET to first-line dual anti-HER2 therapy post chemotherapy in patients with HER2 + /HR + MBC was associated with major gains in PFS and OS with no safety concerns evident. Further studies of this combination are justified, along with studies of how best to integrate other agents that are active in this patient subset, including CDK4/6 inhibitors.

Pertuzumab study in the neoadjuvant setting for HER2-positive nonmetastatic breast cancer in Australia (PeRSIA).

The pertuzumab study in the neoadjuvant setting for HER2+ nonmetastatic breast cancer in Australia (PeRSIA-ML39622) is an analysis of safety and effectiveness data from the pertuzumab patient registry. Although the prognosis of patients with early stage HER2+ breast cancer has been greatly improved by advances in chemotherapy approximately 25% to 30% of patients develop recurrent disease. Our study aimed to examine the effectiveness of neoadjuvant pertuzumab on surgical outcomes, describe the medium-term effectiveness outcomes of patients treated with pertuzumab, and describe the planned and actual anticancer treatment regimens that patients received. Deidentified data were collected from the patients' medical records and entered into REDCap, between March 2018 and July 2019 (n = 95). The adverse events (AEs) reported most frequently were diarrhea (20; 21.1%), rash (4; 4.2%), and LVSD (4; 4.2%; two patients during neoadjuvant treatment and two patients during adjuvant treatment). AEs, ≥Grade 3 were diarrhea (2; 2.1%) and LVSD (1; 1.1%). Following surgery, a breast pathological complete response (bpCR) was achieved in 65 patients (70.7%; 95% CI: 60.2%-79.7%) and total pathological complete response (tpCR) in 59 patients (64.1%; 95% CI: 53.4%-73.9%). All patients who did not achieve a tpCR obtained a partial response (33/92, 35.9%). Our study is the first to capture real-world data on the use of pertuzumab in the neoadjuvant setting in Australia. The effectiveness and safety data are consistent with those reported in clinical trials of pertuzumab in patients with HER2+ breast cancer, with no new safety concerns.

COVID-19 Vaccine Hesitancy in Australian Patients with Solid Organ Cancers.

BACKGROUND: Vaccination is the cornerstone of the global public health response to the COVID-19 pandemic. Excess morbidity and mortality of COVID-19 infection is seen in people with cancer. COVID-19 vaccine hesitancy has been observed in this medically vulnerable population, although associated attitudes and beliefs remain poorly understood. METHODS: An online cross-sectional survey of people with solid organ cancers was conducted through nine health services across Australia. Demographics, cancer-related characteristics and vaccine uptake were collected. Perceptions and beliefs regarding COVID-19 vaccination were assessed using the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale-6. RESULTS: Between June and October 2021, 2691 people with solid organ cancers completed the survey. The median age was 62.5 years (SD = 11.8; range 19-95), 40.9% were male, 71.3% lived in metropolitan areas and 90.3% spoke English as their first language. The commonest cancer diagnoses were breast (36.6%), genitourinary (18.6%) and gastrointestinal (18.3%); 59.2% had localized disease and 56.0% were receiving anti-cancer therapy. Most participants (79.7%) had at least one COVID-19 vaccine dose. Vaccine uptake was higher in people who were older, male, metropolitan, spoke English as a first language and had a cancer diagnosis for more than six months. Vaccine hesitancy was higher in people who were younger, female, spoke English as a non-dominant language and lived in a regional location, and lower in people with genitourinary cancer. Vaccinated respondents were more concerned about being infected with COVID-19 and less concerned about vaccine safety and efficacy. CONCLUSIONS: People with cancer have concerns about acquiring COVID-19, which they balance against vaccine-related concerns about the potential impact on their disease progress and/or treatment. Detailed exploration of concerns in cancer patients provides valuable insights, both for discussions with individual patients and public health messaging for this vulnerable population.

Real-World Outcomes of Ribociclib and Aromatase Inhibitor Use in First Line Hormone Receptor Positive, HER2-Negative Metastatic Breast Cancer.

BACKGROUND: International guidelines recommend combining a CDK4/6 inhibitor and endocrine therapy (ET) as first line treatment for hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Results from MONALEESA-2 demonstrate superior progression free survival (PFS) and overall survival (OS) with ribociclib (CDK4/6 inhibitor) and ET compared to ET alone. Real world outcomes have yet to be reported. MATERIALS AND METHODS: KARMA is a non-interventional registry of Australian patients receiving first-line treatment with ribociclib and aromatase inhibitor (AI), obtained via a Medicine Access Program (MAP) for HR+, HER2- MBC. Outcomes were compared with the ribociclib/letrozole cohort in MONALEESA-2. RESULTS: Data from 160 patients at 17 sites was analysed. Median follow-up is 36.5 months. Compared to MONALEESA-2, patients were numerically younger (54.3 vs. 62 years), with higher rates of bone-only metastases (31% vs. 21%). A total of 63 of 160 (39%) patients remain on treatment. A total of 56% of patients had at least 1 dose reduction, with neutropenia (68%) and abnormal liver enzymes (17%) the most common reasons. A total of 17 of 160 (11%) discontinued treatment due to toxicity, with no treatment related deaths. Median PFS was not reached (95% CI 29.9- NR), with PFS at 12 months and 18 months being 76% and 67% respectively versus 25.3 months, 73% and 63% in MONALEESA-2. CONCLUSION: The ribociclib and AI combination was well tolerated in this real-world setting. The KARMA registry cohort achieved a superior PFS (>36.5 months) to MONALEESA-2, potentially due to more favourable baseline disease characteristics. Less frequent assessment scheduling in this non trial setting may also contribute.

Real-World Outcomes in Patients With Brain Metastases Secondary to HER2-Positive Breast Cancer: An Australian Multi-centre Registry-based Study.

BACKGROUND: The development of brain metastases occurs commonly in HER2-positive metastatic breast cancer and is associated with a poorer prognosis. The advent of HER2-targeted therapy has improved overall survival, but the benefit in patients with brain metastases is unclear, as these patients are often excluded from clinical trials. This study aimed to explore real-world outcomes in patients with brain metastases in HER2-positive MBC. MATERIALS & METHODS: Data was extracted from the TABITHA registry, which consists of patient data collected prospectively from 16 Australian sites from 24th February 2015 to 31st October 2021. Data analysed included characteristics of brain metastases, treatment received and survival outcomes. RESULTS: A total of 135 (37%) of 361 patients with HER2-positive MBC were diagnosed with brain metastases during their clinical course, including 45 (12%) with brain metastases at time of MBC diagnosis. 61 (45%) had ≥4 brain lesions. The most common local therapy given was whole brain radiation therapy (WBRT) (36%) followed by multi-modality treatment with both surgery and radiation therapy (27%). The majority of patients received first-line HER2-targeted treatment with trastuzumab and pertuzumab followed by second-line trastuzumab emtansine (T-DM1) but third-line therapy was heterogenous. The median overall survival in patients who developed brain metastases was significantly shorter than those who did not develop brain metastases (58.9 vs. 96.1 months, P = .02). CONCLUSION: Real-world patients diagnosed with brain metastases in HER2-positive MBC have a relatively poor prognosis, despite advances in HER2-targeted treatment. As the range of HER2-targeted treatment expands, it is important to pursue clinical trials that focus on patients with brain metastases.

Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer.

BACKGROUND: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. METHODS: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. RESULTS: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. CONCLUSIONS: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

Serious Underlying Medical Conditions and COVID-19 Vaccine Hesitancy: A Large Cross-Sectional Analysis from Australia.

As COVID-19 vaccinations became available and were proven effective in preventing serious infection, uptake amongst individuals varied, including in medically vulnerable populations. This cross-sectional multi-site study examined vaccine uptake, hesitancy, and explanatory factors amongst people with serious and/or chronic health conditions, including the impact of underlying disease on attitudes to vaccination. A 42-item survey was distributed to people with cancer, diabetes, or multiple sclerosis across ten Australian health services from 30 June to 5 October 2021. The survey evaluated sociodemographic and disease-related characteristics and incorporated three validated scales measuring vaccine hesitancy and vaccine-related beliefs generally and specific to their disease: the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale-Six. Among 4683 participants (2548 [54.4%] female, 2108 [45.0%] male, 27 [0.6%] other; mean [SD] age, 60.6 [13.3] years; 3560 [76.0%] cancer, 842 [18.0%] diabetes, and 281 [6.0%] multiple sclerosis), 3813 (81.5%) self-reported having at least one COVID-19 vaccine. Unvaccinated status was associated with younger age, female sex, lower education and income, English as a second language, and residence in regional areas. Unvaccinated participants were more likely to report greater vaccine hesitancy and more negative perceptions toward vaccines. Disease-related vaccine concerns were associated with unvaccinated status and hesitancy, including greater complacency about COVID-19 infection, and concerns relating to vaccine efficacy and impact on their disease and/or treatment. This highlights the need to develop targeted strategies and education about COVID-19 vaccination to support medically vulnerable populations and health professionals.

Complementary Medicine Use Amongst Patients with Metastatic Cancer Enrolled in Phase III Clinical Trials.

BACKGROUND: Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown. METHODS: Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups. RESULTS: Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of life was similar between both groups. After adjustment with propensity score matching, CM use was also associated with longer overall survival in patients with lung cancer (adjusted hazard ratio 0.80, 95%CI, 0.68-0.94, P =.0054). However, several key control variables like EGFR status were not available. CONCLUSION: One in 5 patients in phase III clinical trials report using CM. CM was not associated with worse cancer-specific outcomes. However, CM users had more favorable baseline prognostic factors, and likely other confounders that may have contributed to improved outcomes observed in the lung cohort. Physicians should monitor for CM use and potential interactions with clinical trial drugs.

Impact of the evolution in RAS mutation analysis in Australian patients with metastatic colorectal cancer.

BACKGROUND: RAS mutation testing now routinely informs the optimal management of metastatic colorectal cancer (mCRC), specifically the finding of a RAS mutation defines patients who will not benefit from treatment with an epidermal growth factor receptor inhibitor. Over time more RAS genes have been tested and more sensitive techniques used. AIMS: To review routine care RAS testing and results over time. METHODS: A retrospective analysis of the molecular data collected prospectively in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry from 2009 to 2018 was undertaken. Patients with RAS data were further analyzed. In parallel, the RAS mutation status of patients enrolled in the Test Tailor Treat (TTT) program was examined for 2011-2018. RESULTS: Of 2908 patients in the TRACC registry, 1892 (65%) were tested, with 898 (47%) of tested patients found to be RAS mutant (RASmt). RAS data were available for 5935 TTT patients. Of the tested TRACC patients diagnosed in 2009 and 2010, 38% were RASmt. For each 2-year period from 2011/2012 through to 2017/2018, the prevalence of RASmt in TRACC and TTT was 42% and 40% (2011/2012), 52% and 40% (2013/2014), 47% and 49% (2015/2016), and 47% and 49% (2017/2018). CONCLUSIONS: Based on both TRACC and TTT data, the proportion of patients reported to have a RAS mutation increased from 2009 to 2015 but has remained relatively stable in recent years. The increased proportion of RASmt patients observed over time is likely largely driven by the uptake of extended RAS testing.

Acute granulomatous interstitial nephritis in a patient with metastatic melanoma on targeted therapy with dabrafenib and trametinib-A case report.

BACKGROUND: Combination molecular targeted therapy with dabrafenib plus trametinib has been shown to improve progression-free survival and overall survival in patients with BRAF V600 mutated unresectable or metastatic melanoma. In general, these agents are well tolerated. Kidney related adverse events are uncommon with only three case reports of acute interstitial nephritis and one case of a serious acute kidney injury. We report another case of interstitial nephritis related to these drugs. CASE: A 37-year-old man diagnosed with metastatic melanoma (BRAF V600E mutation) who developed acute interstitial nephritis 5 years into his treatment with combination dabrafenib plus trametinib therapy. He presented with an asymptomatic acute kidney injury on routine surveillance pathology with a creatinine of 174 µmol/L (from baseline 80 µmol/L) and a corresponding estimated glomerular filtration rate (eGFR) of 42 ml/min/1.73 m2 (from a baseline >90 ml/min/1.73 m2 ) and microalbuminuria (albumin creatinine ratio [ACR] 8.5 mg/mmol). Renal biopsy revealed a granulomatous interstitial nephritis likely drug related. He was treated with prednisolone 1 mg/kg and ceased his targeted therapy with improvement in his renal function. CONCLUSION: Although rare, recognition of acute interstitial nephritis, a possible serious adverse outcome due to dabrafenib and trametinib is important and needs to be incorporated into current Australian cancer therapy guidelines.

Patient demographics and management landscape of metastatic colorectal cancer in the third-line setting: Real-world data in an australian population.

BACKGROUND: Colorectal cancer is the third most common cancer and second leading cause of cancer mortality in Australia, thus carrying a significant disease burden. AIMS: This analysis aims to explore real-world treatment landscape of metastatic colorectal cancer in the third-line setting. METHODS: We retrospectively analysed treatment of recurrent and advanced colorectal cancer (TRACC) registry database from 2009 onwards. Patients treated with palliative intent who progressed after two lines of therapies were included. One treatment line was defined as any combination of systemic therapy given until progression. RESULTS: Out of 1820 patients treated palliatively, 32% (590 patients) met study criteria. Of these, 43% (254 patients) proceeded to third-line therapy, equating to 14% of all metastatic patients. In KRAS mutant or unknown tumours (97 patients), fluoropyrimidine (FP)-oxaliplatin combination was the most common choice (51%), followed by FP-irinotecan (15%), trifluridine/tipiracil (11%), mono-chemotherapy (10%), regorafenib (5%) and others (7%). Majority of FP-doublet (83%) was given as rechallenge. In 157 patients with KRAS wildtype disease, monotherapy with EGFR inhibitor was most commonly used (41%), followed by EGFR inhibitor with chemotherapy (20%), FP-doublet (18%), mono-chemotherapy (6%), trifluridine/tipiracil (6%), regorafenib (1%) and others (8%). Median overall survival was 7.1 months (range 0.4-41.2), and median time on third-line treatment was 3 months (range 0.1-40). CONCLUSIONS: In real-world Australian population, treatment choices differed based on KRAS status and will likely change with the availability of newer drugs on the pharmaceutical benefits scheme. Survival outcomes are comparable to newer agents in clinical trials for select patients.

Uptake of bone-modifying agents in patients with HER2+ metastatic breast cancer with bone metastases - prospective data from a multi-site Australian registry.

BACKGROUND: International practice guidelines recommend administration of bone-modifying agents (BMA) in metastatic breast cancer (MBC) patients with bone metastases to reduce skeletal-related events (SRE). Optimal delivery of BMA in routine clinical practice, including agent selection and prescribing intervals, remains unclear. AIM: To describe real-world practice of Australian breast oncologists. METHODS: Prospective data from February 2015 to July 2020 on BMA delivery to MBC patients with bone metastases was analysed from Treatment of Advanced Breast Cancer in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Australian Patient (TABITHA), a multi-site Australian HER2+ MBC registry. RESULTS: Of 333 HER2+ MBC patients, 171 (51%) had bone metastases at diagnosis, with a mean age of 58.1 years (range, 32-87). One hundred and thirty (76%) patients received a BMA, with 90 (69%) receiving denosumab and 40 (31%) receiving a bisphosphonate. Patients who received a BMA were more likely to have received concurrent first-line systemic anti-HER2 therapy (95% vs 83%; P = 0.04), to present with bone-only metastases at diagnosis (24% vs 7%; P = 0.02) and less likely to have visceral metastases (51% vs 71%; P = 0.03). Ten of 40 (25%) bisphosphonate patients and 45 of 90 (50%) denosumab patients received their BMA at the recommended 4-weekly interval. Prescribing intervals varied over time. Adverse events reported were consistent with clinical trial data. CONCLUSION: Three-quarters of Australian HER2+ MBC patients with bone metastases receive a BMA, often at different schedules than guidelines recommend. Further studies, including all MBC subtypes, are warranted to better understand clinicians' prescribing rationale and potential consequences of current prescribing practice on SRE incidence.

Treatment and Outcomes of Oligometastatic Colorectal Cancer Limited to Lymph Node Metastases.

INTRODUCTION: The optimal management of isolated distant lymph node metastases (IDLNM) from a colorectal primary, is not clearly established. We aimed to analyze the outcomes of patients with IDLNM treated with systemic therapies plus locoregional therapy with curative intent versus systemic therapies with palliative intent. MATERIALS & METHODS: Clinical data were collected and reviewed from the Treatment of Recurrent and Advanced Colorectal Cancer registry, a prospective, comprehensive registry for metastatic colorectal cancer (mCRC) treated at multiple tertiary hospitals across Australia. Clinicopathological characteristics, treatment modalities and survival outcomes were analyzed in patients with IDLNM and compared to patients with disease at other sites. RESULTS: Of 3408 mCRC patients diagnosed 2009 to 2020, with median follow-up of 38.0 months, 93 (2.7%) were found to have IDLNM. Compared to mCRC at other sites, patients with IDLNM were younger (mean age: 62.1 vs. 65.6 years, P = .02), more likely to have metachronous disease (57.0% vs. 38.9%, P < .01), be KRAS wild-type (74.6% vs. 53.9%, P< .01) and BRAF mutant (12.9% vs. 6.2%, P = .01). Amongst mCRC patients with IDLNM, 24 (25.8%) received treatment with curative intent and had a significantly better overall median survival than those treated with palliative intent (73.5 months vs. 23.2 months, P = .01). These 24 patients had an overall median survival similar (62.7 months, P = .82) to patients with isolated liver or lung metastases also treated with curative intent. CONCLUSION: Curative treatment strategies (radiotherapy or surgery), with or without systemic therapy, should be considered for mCRC patients with IDLNM where appropriate as assessed by the multidisciplinary team.

BRAFV600E Mutations Arising from a Left-Side Primary in Metastatic Colorectal Cancer: Are They a Distinct Subset?

BACKGROUND: B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary. OBJECTIVES: To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS. RESULTS: Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p < 0.0001), and inferior OS (median 15.1 vs. 36.6 months; p < 0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively. CONCLUSION: LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.

Metastasectomy and BRAF mutation; an analysis of survival outcome in metastatic colorectal cancer.

BACKGROUND: Resection of oligometastases improves survival in metastatic colorectal cancer (mCRC). It is unclear whether the benefit is consistent for BRAF V600E mutant (MT) and wild type (WT) mCRC. This retrospective analysis explores the influence of BRAF MT on survival after metastasectomy. METHODS: Overall survival (OS) and recurrence-free survival (RFS) for BRAF MT and WT mCRC were evaluated. Survival was also analyzed in the cohort of BRAF MT with or without metastasectomy. RESULTS: Five hundred and thirteen patients who had undergone metastasectomy were identified, 6% were BRAF-MT. Median age 63. Median OS in BRAF MT vs WT: 25.7 vs 48.5 months (hazard ratio [HR] 1.95; 1.18-3.22). However, difference was not significant in a multivariate model. Right primary tumor, intact primary, >1 metastatic site, non-R0 resection, peritoneal metastasis, and synchronous metastasis were independent predictors of worse OS. Among 364 patients with RFS data there was no difference between BRAF MT and WT (16 vs 19 months, p=0.09). In another cohort of 158 BRAF-MT patients, OS was significantly better after metastasectomy compared to "no metastasectomy" (HR 0.34; 0.18-0.65, P= 0.001). Proficient mismatch repair status showed a trend toward worse survival after metastasectomy in BRAF MT (HR 1.71, P = 0.08). CONCLUSION: OS did not differ after metastasectomy between BRAF MT and WT in a multivariate model. Median OS was >2 years in this study after metastasectomy among BRAFV600E MT patients suggesting a survival benefit of metastasectomy in this group where systemic therapeutic options are limited. Metastasectomy may be considered in carefully selected BRAF-MT patients.