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Introduction Neoadjuvant radiotherapy (NART) as part of a multi-modality approach for locally advanced breast cancer (LABC) requires further investigation. Importantly, this approach may allow for a single-staged surgical procedure, with mastectomy and immediate autologous reconstruction. Multiple other potential benefits of NART include improved pathological downstaging of breast disease, reduced overall treatment time, elimination of time period with breast tissue deficit and improved patient satisfaction. Methods This is a retrospective multi-institutional review of patients with LABC and high-risk breast disease undergoing NART. Eligible patients sequentially underwent neoadjuvant chemotherapy (NACT) with or without HER2-targeted therapy, NART, followed by mastectomy with immediate autologous breast reconstruction (BR) 4- to 6 weeks post-completion of radiotherapy. Patient and tumour characteristics were analysed using descriptive statistics. Surgical complications were assessed using the Clavien-Dindo Classification (Ann Surg 2004; 240: 205). Results From 3/2013 to 9/2019, 153 patients were treated with NART. The median age was 47 years (IQR 42-52), with median body mass index of 27. Eighteen patients experienced Grade 3 acute surgical complications. This included 13 Grade 3B breast-site events and 9 Grade 3B donor-site events, where further surgical intervention was required for management of wound infection, wound dehiscence, flap or mastectomy skin necrosis, haematoma and internal mammary venous anastomotic thrombosis. No autologous flap loss was observed. Conclusion Neoadjuvant radiotherapy facilitates a single-stage surgical procedure with mastectomy and immediate autologous BR, eliminating the delay to reconstructive surgery and thus shortening a woman's breast cancer journey. The findings of this review support the use of NART, with comparable rates of surgical complications to standard sequencing.

Background Tucatinib (TUC) is a highly selective oral tyrosine kinase inhibitor of HER2 with minimal inhibition of EGFR. It was recently approved by the FDA for patients (pts) with HER2+ metastatic breast cancer (MBC), including pts with brain metastases (BM) whose cancers have progressed on at least 1 prior anti-HER2 regimen in the metastatic setting. In the HER2CLIMB (NCT02614794) pivotal trial, pts with HER2+ MBC previously treated with trastuzumab (T), pertuzumab, and trastuzumab emtansine (T-DM1) were randomized to receive TUC or placebo in combination with T and capecitabine (C). The addition of TUC resulted in clinically meaningful and statistically significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in HER2+ MBC pts. Primary methods and outcomes have been reported previously (Murthy, NEJM 2019). Here we present an exploratory analysis describing the outcomes in the HER2CLIMB trial based on hormone receptor (HR) status. Methods Pts were randomized 2:1 to receive TUC or placebo in combination with T and C. All pts had a baseline brain MRI and randomization was stratified by presence of BM, ECOG status, and geographic region. All pts with HER2+ MBC who were positive for either or both estrogen receptor and progesterone receptor (> 1%) were assigned to the HR “positive” subgroup. Pts not meeting the above criteria were assigned to the HR “negative” subgroup. For the exploratory HR+/HR- efficacy analysis presented here, PFS per RECIST 1.1 by blinded independent central review was evaluated in the first 480 pts enrolled. OS, PFS in pts with baseline BM, and confirmed ORR in pts with measurable disease were evaluated in the total study population. P values presented for PFS are nominal. Results Overall, 612 pts were enrolled to HER2CLIMB; 370 pts (60%) had HR+ and 242 (40%) had HR- tumors. Baseline demographics and disease characteristics in HR+/HR- subgroups were generally balanced between treatment arms. In the HR+ group, there was a 42% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.58; 95% CI: 0.42, 0.80; P=0.0008); median (95% CI) PFS was 7.6 mo (7.4, 9.5) in the TUC arm vs 5.6 mo (4.3, 7.4) in the control arm. In the HR- group, there was a 46% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.54; 95% CI: 0.34, 0.86; P=0.008); median (95% CI) PFS was 8.1 mo (7.0, 11.6) in the TUC arm vs 4.2 mo (3.1, 8.6) in the control arm. In the total population, median OS was 21.7 mo vs 18.2 mo in HR+ in the TUC arm vs control arm, respectively; median OS in HR- was 31.1 mo in the TUC arm vs 14.1 mo in the control arm. In pts with BM in the HR+ group (n=166 [45%]), there was a 52% reduction in the risk of progression or death (hazard ratio: 0.48; 95% CI: 0.31, 0.75; P=0.0008); median (95% CI) PFS was 7.5 mo (5.6, 9.5) in the TUC arm vs 5.1 mo (4.1, 5.7) in the control arm, and median OS was 18.1 mo vs 12.8 mo, respectively. In pts with BM in the HR- group (n=125 [52%]), there was a 50% reduction in the risk of progression or death (hazard ratio: 0.50; 95% CI: 0.27, 0.95; P=0.03); median (95% CI) PFS was 7.8 mo (6.1, 11.6) in the TUC arm vs 5.4 mo (2.9, 8.6) in the control arm, and median OS was 18.5 mo vs 11.5 mo, respectively. In the total population, ORR was numerically higher in the TUC arm vs the control arm regardless of HR status (HR+: 37.4% [95% CI: 30.8, 44.5] vs 27.1% [95% CI: 19.0, 36.6], respectively and HR-: 45.3% [95% CI: 36.7, 54.0] vs 15.6% [95% CI: 7.8, 26.9], respectively). Conclusions Among pts with HER2+ MBC previously treated with T, pertuzumab, and T-DM1, the addition of TUC to T and C showed clinically meaningful improvements of PFS, OS, and ORR independent of HR status. Furthermore, pts with HR+ and HR- MBC with BM derived similar benefit from the addition of TUC to T and C. Citation Format: Erika Hamilton, Mattea Reinisch, Sherene Loi, Alicia Okines, Paula R. Pohlmann, Eva Harder Brix, Hugues Bourgeois, Belinda Yeo, Cheryl Aylesworth, Melody Cobleigh, Anthony Goncalves, Rebecca Moroose, Katherine H.R. Tkaczuk, Michaela Tsai, Christine Simmons, Michael Andersson, Hatem Soliman, Michelina Cairo, Lisa A. Carey, David Cameron, Jorge Ramos, Wentao Feng, Mafalda Oliveira. Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-08.

BackgroundThe development of anti-human epidermal growth factor receptor 2 (HER2) therapies has significantly improved disease outcomes in patients with HER2-positive advanced breast cancer (ABC). However, elderly patients are persistently under-represented in clinical trials, with only 2.4% of patients aged ≥75 years in the pivotal CLEOPATRA study. Despite a lack of research addressing treatment outcomes in elderly patients, advanced age at diagnosis is associated with a greater likelihood of receiving no initial systemic therapy for de novo metastatic breast cancer. Studies have also shown that older women diagnosed with metastatic breast cancer have a poorer prognosis and shorter life expectancy. We examined treatment patterns and outcomes in an elderly (defined as ≥70) ‘real world’ Australian population. MethodsData was extracted from the Treatment of Advanced Breast Cancer in the HER2-positive Australian Patient (TABITHA) multi-site clinical registry, and patients stratified according to age ( ResultsWe identified 319 patients, including 67 patients (21%) aged ≥70 years. Older patients were more likely to have an Eastern Cooperative Oncology Group performance status of ≥2 (16% vs 3%; p ConclusionElderly patients with HER2-positive ABC demonstrated shorter chemotherapy durations, poorer overall survival, and increased rates of adverse events despite having similar disease characteristics and treatment patterns. Prospective studies are required to improve outcomes in the elderly HER2 positive population. Citation Format: Nicole Evans, Angelyn Anton, Rachel Wong, Sheau Wen Lok, Richard De Boer, Laeeq Malik, Sally Greenberg, Belinda Yeo, Louise Nott, Gary Richardson, Ian M Collins, Javier Torres, Frances Barnett, Peter Gibbs, Bianca Devitt. Real world outcomes in elderly women with HER2 positive advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-35.

BACKGROUND: A history of cancer is incorporated into the surgical risk assessment of patients undergoing surgical aortic valve replacement through the Society for Thoracic Surgeons score. However, the prognostic significance of cancer in patients treated with transcatheter aortic valve replacement (TAVR) is unclear. As the cancer survivorship population increases, it is imperative to establish the efficacy and safety of TAVR in patients with severe symptomatic aortic stenosis (AS) and a history of malignancy. OBJECTIVES: The primary goal of this study was to assess the periprocedural outcomes and long-term mortality in patients with a history of cancer undergoing TAVR. METHODS: A systematic review of PubMed, MEDLINE, and EMBASE was conducted to identify studies reporting outcomes in patients with a history of malignancy undergoing TAVR. A meta-analysis was performed using a random-effects model with a primary outcome of all-cause mortality and cardiac mortality at the longest follow-up. On secondary analyses, procedural safety was assessed. RESULTS: A total of 13 observational studies with 10,916 patients were identified in the systematic review. Seven studies including 6,323 patients were included in the quantitative analysis. Short-term mortality (relative risk [RR] 0.61, 95%CI 0.36-1.01; p = .06) and long-term all-cause mortality (RR 1.24, 95%CI 0.95-1.63; p = .11) were not significantly different when comparing patients with and without a history of cancer. No significant difference in the rate of periprocedural complications including stroke, bleeding, acute kidney injury, and pacemaker implantation was noted. CONCLUSION: In patients with severe AS undergoing TAVR, a history of cancer was not associated with adverse short or long-term survival. Based on these findings, TAVR should be considered in all patients with severe symptomatic AS, irrespective of their history of malignancy.

Background: HER2 targeted therapies, such as trastuzumab, pertuzumab and trastuzumab-emtansine (TDM-1), have improved survival of patients (pts) with HER2+ metastatic breast cancer (MBC). In the pivotal phase III study of pertuzumab/trastuzumab/docetaxel in MBC (NCT00567190), only 10% of pts received prior trastuzumab, whereas in modern practice the majority of recurrent HER2+ MBC pts have received neo(adjuvant) trastuzumab [NAT]. Survival outcomes in the real world setting have not been well described. Methods: Pts were part of a prospective national registry collecting clinicopathologic, treatment and outcome data for HER2+ MBC pts diagnosed between 10/2006 and 1/2019. Survival was estimated by the Kaplan-Meier method and compared among groups by log-rank test. A multivariable analysis was used to assess the impact of prior trastuzumab-use on survival. Analysis was stratified by estrogen receptor (ER) status to exclude the impact of concurrent endocrine therapy in the ER positive (ER+) subgroup. The TABITHA registry is sponsored by BioGrid Australia with financial support from Roche Products Pty Limited. Results: Of 254 HER2+ MBC pts in the registry, 225 received HER2 directed therapy in the first-line advanced disease setting and were included for analysis. Median age was 58 years, 100 (44%) had de novo metastatic disease, 131 (58%) had ER+ disease and 24 (11%) had brain metastases. Of the 125 (56%) pts with recurrent disease, 89 (71%) pts received NAT. First-line HER2 therapy was pertuzumab plus trastuzumab in 176 (78%), trastuzumab in 38 (17%), TDM-1 in 9 (4%), and lapatinib or pertuzumab alone in single pts ( The response rate to anti-HER2 therapy among all MBC pts evaluable for response was 42% in pts who received NAT, and 53% in pts who did not (p=0.20). Median progression free survival (PFS) was 16.4 months and 22.6 months, in pts who were trastuzumab-treated and trastuzumab-naïve, respectively (HR 1.44 [95%CI 0.99 - 2.10], p=0.05). The median overall survival (OS) from first-line HER2-directed therapy for MBC was 41.2 months in pts who had prior NAT, and 52.0 months in trastuzumab-naïve pts (HR 1.73 [95%CI 1.04 - 2.86], p=0.03). On multivariable analysis, prior trastuzumab-exposure was no longer significantly associated with survival. Factors significantly associated with PFS were ER status (HR 0.63, p=0.02) and age (HR 1.02, p=0.04), while only age was significantly associated with OS (see table). Among the subset of 93 ER negative (ER-) pts, prior NAT was significantly associated with inferior PFS (HR 1.97 [95%CI 1.11 - 3.52], p=0.02) and OS (HR 2.13 [95% CI 1.00 - 4.57], p=0.046). Multivariable analysis found only age and presence of brain metastases to be significantly associated with OS in the ER- subgroup. NAT exposure did not impact on PFS (HR 1.15, [95% CI 0.70 - 1.90], p=0.58) or OS (HR 1.37, [95% CI 0.68 - 2.73], p=0.37) in ER+ pts. Conclusions: In pts with HER2+ MBC, receipt of NAT was associated with inferior survival when HER2 targeted therapy was used in the metastatic setting on univariate analysis, but this finding was not seen in a multivariable analysis. Furthermore, the impact of NAT was only observed in the subset of pts with ER- tumors, raising the possibility that the disease-course in ER+ subgroup is not entirely HER2 driven. Survival rates of these HER2+ MBC pts treated in the community are comparable to that reported in clinical trials. Cox proportional hazard models for OS in MBC on HER2-targeted therapyUnivariableMultivariableHR95% CIPHR95% CIPAdjuvant trastuzumab Y vs N1.731.04 – 2.850.031.370.64 – 2.940.42De novo metastatic disease Y vs N0.610.37 – 1.020.060.810.38 – 1.730.59Estrogen receptor positive vs negative0.880.53 – 1.440.600.690.41 – 1.180.18Brain metastases Y vs N1.800.88 – 3.670.111.960.90 – 4.260.09Age (years)1.021.00 – 1.040.051.031.01 – 1.060.003 Citation Format: Yada Kanjanapan, Dan Tran, Sheau Wen Lok, Peter Gibbs, Richard De Boer, Belinda Yeo, Sally Greenberg, Frances Barnett, Louise Knott, Gary Richardson, Rachel Wong, Michelle Nottage, Ian Collins, Javier Torres, Janine Lombard, Julie Johns, Michael Harold, Laeeq Malik. Impact of prior (neo)adjuvant trastuzumab exposure on the efficacy of HER2 targeted therapy for metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-13.

Radiation therapy (RT) is an established treatment for breast cancer and is associated with a reduction in disease recurrence and death. Thoracic RT is associated with incidental cardiac exposure, which can lead to a spectrum of radiation-induced heart disease (RIHD) ([1][1]). The mechanisms

Optical barcoding reveals enhanced TNFα activation and polyclonality in lung, but not liver, metastases from breast cancer., Intratumoral heterogeneity is a driver of breast cancer progression, but the nature of the clonal interactive network involved in this process remains unclear. Here, we optimized the use of optical barcoding to visualize and characterize 31 cancer subclones in vivo. By mapping the clonal composition of thousands of metastases in two clinically relevant sites, the lungs and liver, we found that metastases were highly polyclonal in lungs but not in the liver. Furthermore, the transcriptome of the subclones varied according to their metastatic niche. We also identified a reversible niche-driven signature that was conserved in lung and liver metastases collected during patient autopsies. Among this signature, we found that the tumor necrosis factor–α pathway was up-regulated in lung compared to liver metastases, and inhibition of this pathway affected metastasis diversity. These results highlight that the cellular and molecular heterogeneity observed in metastases is largely dictated by the tumor microenvironment.

Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-secreted vesicles, especially exosomes, have recently been implicated in the guidance of metastatic dissemination, with specific surface composition determining some aspects of organ-specific localization. Nevertheless, whether the tumor microenvironment influences exosome biodistribution has yet to be investigated. Here, we show that microenvironmental cytokines, particularly CCL2, decorate cancer exosomes via binding to surface glycosaminoglycan side chains of proteoglycans, causing exosome accumulation in specific cell subsets and organs. Exosome retention results in changes in the immune landscape within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a crucial determinant of exosome-cell interactions. In addition to the finding that cytokine-conjugated exosomes are detected in the blood of cancer patients, we discovered that healthy subjects derived exosomes are also associated with cytokines. Although displaying a different profile from exosomes isolated from cancer patients, it further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings., Cancer derived exosomes are reported to promote metastatic dissemination. Here the authors show that cytokines in the tumor microenvironment bind to exosomes via glycosaminoglycan side chains of proteoglycans, and these exosomes are preferentially taken up by specific cell lineages and organs to promote metastasis.

Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0–8) were treated with daily tamoxifen (20 mg) and venetoclax (200–800 mg). Apart from uncomplicated “on-target” lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and the clinical benefit rate was 75%. Treatment responses were preempted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations. Significance: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors. See related commentary by Drago et al., p. 323. This article is highlighted in the In This Issue feature, p. 305

Background: Aromatase inhibitors (AI), which block the conversion of androgen to estrogen, are the mainstay therapy for estrogen receptor–positive (ER+) breast cancer (BC). However, many patients relapse. Purpose: To identify molecular alterations associated with long-term neoadjuvant AI therapy of ER+ BC. Methods: We retrospectively identified 137 patients diagnosed with ER+ BC and treated with neoadjuvant AI for at least 1 month at the Royal Marsden Hospital (2003–2016). Paired pre- (diagnosis) and post-AI (surgery) biopsies with >40% invasive cell areas were available from 87 ER+ BC patients. In all samples, we evaluated ER, PR and Ki67 immunostaining, ESR1 hot-spot mutations by droplet digital PCR and expression of 801 genes associated with BC and response to endocrine therapy by NanoString. Results: Mean time on neoadjuvant treatment was 26 weeks (range 5.6–92.3). Cell proliferation remained suppressed in most tumours indicating little evidence for acquired resistance: 56/87 (64%) showed residual Ki67 (Ki67r) 10%. This was paralleled by reduced expression of proliferation genes, ER (immunostaining and gene expression) and estrogen-regulated genes (ERG) at surgery compared with the diagnostic samples (all p6 months, giving a prevalence in this cohort of 5/34 (15%). Tumours with ESR1 mutations showed less suppression of ERGs (p=0.002) and proliferation (p=0.039) and increased ESR1 (p=0.016) expression at surgery compared with tumours without mutation. Pathway analysis confirmed lack of inhibition of estrogen response (FDR>5%) and less inhibition of cell cycle [enrichment score: -0.49 vs -0.78) and E2F targets (-0.47 vs -0.8) in tumours with mutation. Tumours without ESR1 mutation but with Ki67r>10% also showed reduced ERGs response (p=0.006) compared to tumours with Ki67r Conclusion: Overall most tumours showed no evidence for the emergence of resistant disease after neoadjuvant AI therapy even after many months of treatment. However, we detected an enrichment of ESR1 mutations (15% of cases) after long-term treatment as a putative driver of ERG expression and proliferation and thus reduced AI response. Therefore, mutant ER appears to be associated with ligand-independent ERG activity supporting the clinical validity of dual blockade with a selective ER down-regulator combined with a CDK4/6 inhibitor targeting the RB/E2F axis in this scenario. Citation Format: Leal MF, Haynes BP, Schuster E, Yeo B, Afentakis M, Dodson A, Buus R, Cheang MC, Martin L-A, Dowsett M. Acquired ESR1 mutation and persistent expression of estrogen regulated genes in ER+ breast cancers on long-term neoadjuvant treatment with aromatase inhibitors [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 P4-15-01.

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.To describe real-world practice of Australian breast oncologists.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.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.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.

Patients presenting with hormone receptor-positive (HR+ ), human epidermal growth factor receptor 2-negative (HER2- ) metastatic breast cancer (MBC) are usually treated with endocrine therapy (ET), except if there is a concern about endocrine resistance or a need to achieve rapid disease control due to visceral crisis. The combination of CDK4/6 inhibitor + ET has now replaced single-agent ET as the standard first-line treatment; and it can also be considered a standard option in the second-line setting. This review briefly summarizes recently reported efficacy findings from the key phase III clinical trials of CDK4/6 inhibitor + ET in patients with HR+ /HER2- MBC, including evidence that adding a CDK4/6 inhibitor to ET improves overall survival and does so without reducing patients' quality of life. There is still much to learn regarding the use of CDK4/6 inhibitors and how they may be optimally integrated into clinical practice. In particular, there is a need for specific biomarkers that help predict the likelihood of response or resistance to CDK4/6 inhibitor therapy; and for data to guide treatment decisions when a patient's disease progresses on a CDK4/6 inhibitor.

AIM The majority of women diagnosed with early breast cancer have hormone-receptor positive (HR+)/HER2-negative disease. Adjuvant endocrine therapy provides substantial risk reduction benefits in virtually all patients. The role of adjuvant chemotherapy in certain subsets of patients is equivocal. This paper sought to evaluate the role of the IHC4+C score to aid this clinical decision in addition to providing an overview of the current molecular and non- molecular tools available in the adjuvant setting. METHODS This prospective study included 53 post-operative HR+/HER2- negative early breast cancer patients selected from the multidiscipliniary team meeting between August 2017 and January 2020. IHC4+C testing was requested by clinicians for patients in whom the availability of the score may have impacted adjuvant decision-making. Adjuvant treatment decisions were recorded at three time points (prior and post IHC4+C scoring as well as the patient's final decision). The primary goal was the proportion of patients who were spared chemotherapy following the availability of IHC4+C scores to impact on clinicians' recommendations for adjuvant systemic therapy. RESULTS A total of 34 patients (64%) were initially recommended to undergo chemotherapy or to consider chemotherapy. With the availability of the IHC4+C score, only 17 patients (32%) underwent chemotherapy, demonstrating a substantial reduction in the frequency of chemotherapy prescribing. CONCLUSION This study demonstrates that when utilized appropriately in a multidisciplinary setting, the IHC4+C algorithm is an alternative, reproducible and affordable tool with a proven capacity to stratify risk and to spare a large proportion of patients from undergoing chemotherapy.

BACKGROUND: Anti-HER2 therapy-related cardiotoxicity is well described in the context of clinical trials, particularly in the setting of early stage disease, but there is more limited data in advanced breast cancer and in the real world setting. MATERIAL AND METHODS: A prospectively-maintained registry database with 312 consecutive patients diagnosed with HER2 positive advanced breast cancer in Australia was analysed. RESULTS: 287 patients (92%) received anti-HER2 therapy, 17 (6%) experienced anti-HER2 therapy-related cardiotoxicity. Patients who experienced cardiotoxicity were more likely to have ≥2 risk factors for cardiotoxicity (OR 3.9 95% CI 1.4-11.3 p = 0.01). A prior diagnosis of cardiovascular disease was significantly associated with cardiotoxicity (OR 7.1 95% CI 1.3-39.5). Cardiotoxicity resolved on imaging in 65% of patients; there was no association between severity and resolution. 11 patients (65%) received cardiologist input. Of the patients who developed cardiotoxicity, 12 patients (71%) received further anti-HER2 therapy in the first- or second-line setting without recurrent cardiotoxicity. DISCUSSION AND CONCLUSION: Therapy-related cardiotoxicity is an uncommon complication of anti-HER2 therapy in the real world setting. Cardiac toxicity resolved in the majority of affected patients, and further anti-HER2 therapy was administered without recurrence of cardiac issues. Our data suggests anti-HER2 therapy can be safely given in routine care, even in patients with risk factors for toxicity.

Granulocyte-colony stimulating factor (G-CSF) is one of several cytokines that can expand and mobilize haematopoietic precursor cells from bone marrow. In particular, G-CSF mobilizes neutrophils when the host is challenged by infection or tissue damage. Severe neutropenia, or febrile neutropenia is a life-threatening event that can be mitigated by administration of G-CSF. Consequently, G-CSF has been used to support patients undergoing chemotherapy who would otherwise require dose reduction due to neutropenia. Over the past 10-15 years it has become increasingly apparent, in preclinical tumour growth and metastasis models, that G-CSF can support tumour progression by mobilization of tumour-associated neutrophils which consequently promote tumour dissemination and metastasis. With the increasing use of G-CSF in the clinic, it is pertinent to ask if there is any evidence of a similar promotion of tumour progression in patients. Here, we have reviewed the preclinical and clinical data on the potential contribution of G-CSF to tumour progression. We conclude that, whilst the evidence for a promotion of metastasis is strong in preclinical models and that limited data indicate that high serum G-CSF levels in patients are associated with poorer prognosis, no studies published so far have revealed evidence of increased tumour progression associated with supportive G-CSF use during chemotherapy in patients. Analysis of G-CSF receptor positive cohorts within supportive trials, as well as studies of the role of G-CSF blockade in appropriate tumours in the absence of chemotherapy could yield clinically translatable findings.

Inflammatory breast cancer is a rare, yet highly aggressive form of breast cancer, which accounts for less than 5% of all locally advanced presentations. The clinical presentation of inflammatory breast cancer often differs significantly from that of noninflammatory breast cancer; however, immunohistochemistry reveals few, if any, distinguishing features. The more aggressive triple-negative and HER2-positive breast cancer subtypes are overrepresented in inflammatory breast cancer compared with noninflammatory breast cancer, with a poorer prognosis in response to conventional therapies. Despite its name, there remains some controversy regarding the role of inflammation in inflammatory breast cancer. This review summarises the current molecular evidence suggesting that inflammatory signaling pathways are upregulated in this disease, including NF-κB activation and excessive IL-6 production among others, which may provide an avenue for novel therapeutics. The role of the tumor microenvironment, through tumor-associated macrophages, infiltrating lymphocytes, and cancer stem cells is also discussed, suggesting that these tumor extrinsic factors may help account for the differences in behavior between inflammatory breast cancer and noninflammatory breast cancer. While there are various novel treatment strategies already underway in clinical trials, the need for further development of preclinical models of this rare but aggressive disease is paramount.

Treatment strategies for hormone receptor-positive (HR+ ), human epidermal growth factor receptor 2-negative (HER2- ) metastatic breast cancer in young women (

Background Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. Patients and methods In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8mg/kg loading dose, then 6mg/kg every 3weeks (q3w)] and pertuzumab (840mg loading dose, then 420mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54years; 29% had received prior trastuzumab. Median treatment duration was 16months for pertuzumab and trastuzumab and 4months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9–22.7] months overall (19.6, 23.0 and 18.1months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%–82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). Conclusions Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. ClinicalTrials.gov NCT01572038.

In women with oestrogen receptor (ER)-positive early breast cancer, oestradiol is important for breast cancer development and progression. Endocrine therapy prevents the deleterious effects of oestradiol in breast tissue by systemically depleting oestradiol concentration (aromatase inhibitors) or preventing its local action in breast tissue (selective oestrogen receptor modulators i.e. tamoxifen), thereby improving oncological outcomes. Use of aromatase inhibitors in postmenopausal women and ovarian function suppression with either tamoxifen or aromatase inhibition in premenopausal women, consequent to systemic oestradiol depletion, exerts detrimental effects on skeletal health. The oestradiol-deficient state causes increased bone remodelling and a negative bone balance. This results in bone loss, microstructural deterioration and bone fragility predisposing to fractures. Similar effects are also seen with tamoxifen in premenopausal women. In contrast, use of tamoxifen in postmenopausal women appears to exert protective effects on bone but studies on fracture risk are inconclusive. The longevity of women with ER-positive breast cancer treated with adjuvant endocrine therapy emphasises the need to mitigate the adverse skeletal effects of these therapies in order to maximise benefit. In general, fractures are associated with increased morbidity, mortality and are a high socioeconomic burden. Whilst the efficacy of antiresorptive therapy in preventing bone mineral density loss in postmenopausal women has been established, further clinical trial evidence is required to provide guidance regarding fracture risk reduction, when to initiate and stop treatment, choice of agent and optimal management of bone health in premenopausal women receiving endocrine therapy. In addition, potential oncological benefits of antiresorptive therapies will also need to be considered.

Estrogen receptor–positive early breast cancer is common and has a relatively good prognosis. It shares risk factors with cardiovascular disease, and cardiovascular disease is an important competing cause of mortality. Adjuvant endocrine therapy with aromatase inhibitors (requiring concomitant ovarian suppression in premenopausal women) or selective estrogen receptor modulators (usually tamoxifen) exert oncologic benefits by respectively inhibiting estradiol synthesis or breast estrogen receptor signaling. Aromatase inhibitors cause systemic estradiol depletion. Tamoxifen has mixed agonistic/antagonistic effects in a tissue-dependent fashion. Given that estrogens modulate cardiometabolic risk, a review of the effects of endocrine therapy on cardiometabolic outcomes is pertinent. The current, but limited, evidence suggests that tamoxifen treatment, although associated with increases in body fat, hepatic steatosis, serum triglycerides, and diabetes risk, modestly reduces low-density lipoprotein cholesterol and lipoprotein(a) and may have favorable effects on markers of subclinical atherosclerosis. Tamoxifen is associated with either no effect on, or a reduction in, cardiovascular events, and it is associated with an increase in venous thromboembolic events. Aromatase inhibitors, although fewer studies are available and often confounded by comparison with tamoxifen, have not been consistently associated with adverse changes in cardiometabolic risk factors or increases in cardiovascular events. Further clinical trials designed to evaluate cardiometabolic outcomes are needed to more accurately determine the effects of endocrine therapy on cardiovascular risks, to inform individualized decisions regarding choice and duration of endocrine therapy, and to implement evidence-based strategies to mitigate cardiometabolic risks. In the meantime, although breast cancer–specific evidence for benefit of lifestyle measures is available and recommended routinely, proactive monitoring and treatment of cardiovascular risk factors should follow general population recommendations.

Background: PgR is only expressed significantly in ER+ breast cancers and is generally considered a classical estrogen-sensitive protein, however, while ER+ cells are almost always expressed in a non-clustered pattern across the tumour bed, PgR+ cells form clusters or clumps with surrounding areas of PgR- cells when assessed by IHC in about 20-25% of PgR+ tumours. This is an ill-described and unexplained feature of intratumoural heterogeneity of a widely measured biomarker. The prognostic significance of the PgR clumpiness is also unknown. Aims: to determine the (i) biologic and (ii) prognostic significance of PgR clumpiness in ER+ primary breast cancer. Methods: (i) Biologic study: 40 primary ER+PgR+ tumours were identified with distinct PgR clumpiness by IHC. Areas of PgR+ and PgR- cells (PgR-rich and PgR-poor areas, respectively) were needle microdissected from unstained sections by juxtaposing them with PgR-stained sections from the same tumour. Areas were also dissected from 8 homogeneous PgR+ and 8 PgR- tumours for reference. NanoString gene expression analysis using a 50-gene code set (45 oestrogen-responsive or proliferation genes + 5 housekeeping genes) was performed on RNA extracts from the samples. (ii) Prognostic study: we developed a PgR heterogeneity score (PgR Het-score, range 0-18) as the product of (A) the number of PgR+ clumps/cm2 of tumour area (range 0 to 6) and (B) the level of overall PgR-positivity (0-4% or 96-100%, score 0; 5-19% or 80-95%, score 1; 20-39 or 60-79%, score 2; 40-59%, score 3). PgR Het-scores were derived from images (Hamamatsu NanoZoomer-XR) of PgR-stained sections from two sets of tumour biopsies taken at diagnosis after which all patients received adjuvant endocrine therapy: 322 tumours from the Royal Marsden and from Southern Sweden collected for a case:control study of risk of recurrence (recurrence:no recurrence, 1:1) and 591 patients from the TransATAC cohort study with time to recurrence as the end-point. Results: (i) Biologic study: In unsupervised hierarchical clustering of RNA expression from all samples, 33/40 pairs of PgR-rich and PgR-poor areas from a single tumour paired together and all 8 positive and negative control samples were grouped separately. Eight genes were differentially expressed between the PgR-rich and -poor areas (FDR Conclusion: Major, functionally significant differences in PgR expression occur within some ER+ tumours that are not explained by differences in ER expression and are not associated with differences in expression of most other estrogen-dependent genes. Further work is on-going to provide a mechanistic explanation for the PgR heterogeneity. Given the discordance in results from the two clinical studies its prognostic significance is uncertain. This work was funded by BCRF. Citation Format: Lila Zabaglo, Richard Buus, Eugene Schuster, Belinda Yeo, Marie Klintman, Ivana Sestak, Jack Cuzick, Ian Smith, Mitch Dowsett. Intratumoural heterogeneity in PgR expression: Molecular and prognostic significance [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-10.

Background: CDK4/6 inhibitors are integral to the treatment of Estrogen Receptor (ER) positive metastatic breast cancer (MBC). Although they are potent inhibitors of proliferation, tumor cell death (by apoptosis) may be curtailed. Venetoclax, an inhibitor of the pro-survival protein BCL2, has shown promise in an early phase clinical trial in ER+ MBC1. Moreover, preclinical studies suggest that venetoclax could improve tumor response to endocrine therapy and a CDK4/6 inhibitor by triggering apoptosis, including in growth arrested/senescent cells2. PALVEN is a phase 1b study (NCT NCT03900884), aiming to combine venetoclax with letrozole and the CDK4/6 inhibitor palbociclib. Trial Design: Eligible patients will be treated with letrozole (2.5 mg), palbociclib (75-125 mg) and venetoclax (100-800 mg) using a 3+3 dose escalation study design, with a maximum of 6 patients per dose cohort. Both palbociclib and venetoclax will be administered on day 1-21 of a 28 day cycle. Dose limiting toxicity (DLT) will be evaluated in the first 4 weeks of treatment. Tumor assessment will be performed every 8 weeks for 24 weeks and then every 12 weeks until progression. The primary endpoint is to describe DLTs reported within the first 4 weeks of treatment and determine the maximum tolerated dose (MTD), in order to define a recommended phase 2 dose (RP2D). Secondary endpoints include type and worst grade adverse events per patient (CTCAE v5.0), tumor response (RECIST v1.1), clinical benefit rate (CBR), progression free and overall survival (PFS, OS) as well as patient reported outcomes. Exploratory endpoints include metabolic response (using FDG-PET), changes in circulating tumor DNA (ctDNA), peripheral blood leukocyte subsets, and tumor phenotype in paired and progression biopsies. Eligibility Women with ER+ (≥10% positively stained carcinoma cells) and BCL2+ (≥50% cells with at least moderate cytoplasmic staining; intensity 2-3 on a 0-3 scale), unresectable locally advanced or MBC are eligible. Patients must have measurable or evaluable disease as per RECIST v1.1 and ECOG performance score of 0-1. Participants must not have had >2 prior lines of treatment in the metastatic setting and no previous treatment with CDK4/6 inhibitor or venetoclax in the adjuvant or metastatic setting. Statistical methods This is a proof-of-concept, dose escalation study and any statistical analysis of responses will be exploratory. Analysis will be focused primarily on adverse events, particularly DLTs reported in the DLT observation period. All secondary endpoints will be analysed separately combining all dosing cohorts. The response rate and CBR will be estimated with 95% confidence intervals calculated using exact methods based on the binomial distribution. Time-to-event endpoints (PFS and OS) will be described using Kaplan-Meier methods to calculate the median survival. Response rate, CBR and time-to-event endpoints (PFS and OS) will also be described for patients treated in the 1st versus 2nd and 3rd line setting. Accrual Target accrual is 6-36, depending on the number of dose cohorts required to reach DLT. Recruitment is active at 2 sites in Australia. References 1 Lok, S.W., et al. (2019). Cancer Discov 9, 354-369. 2 Whittle, J.R., et al. (2020). Clin Cancer Res Advance online. Citation Format: Christine Muttiah, Avraham Travers, James R Whittle, Sarah-Jane Dawson, Belinda Yeo, Jane E Visvader, Catherine Oakman, Geoffrey J Lindeman. PALVEN: A phase 1b study of palbociclib, letrozole and venetoclax in estrogen receptor, BCL2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-27-01.

Background Trastuzumab has changed the natural history of metastatic HER2 positive breast cancer. Some patients remain well and in remission for many years. There is currently no established duration after which trastuzumab in the advanced setting can be safely discontinued. This study aims to evaluate long-term efficacy and cardiac safety of trastuzumab when used as first-line treatment for patients with metastatic HER2 positive breast cancer. Patient and methods We retrospectively identified 215 patients with HER2 positive, locally advanced or metastatic breast cancer who commenced first line trastuzumab-containing therapy for metastatic disease between 2001 and 2010 at The Royal Marsden Hospital. Results The median progression free survival for all patients was 12 months (95%CI: 10.3–14.6 months); 103 (48%) patients remained in remission beyond one year, 59 (27%) beyond two years and 25 (12%) beyond five years. The median overall survival was 2.6 years (95% confidence interval (CI): 2.2–3.3). The objective response rate (ORR) was 65% with 17 (8%) complete responses and 120 (57%) partial responses. Trastuzumab was well tolerated. Twenty eight (13%) patients recorded any grade of left ventricular dysfunction. There was no significant difference in cardiac toxicity between those patients on less than or more than one year of trastuzumab. Conclusion Trastuzumab is associated with long-term remissions in a significant proportion of patients with metastatic HER2 positive disease when used in the first-line advanced setting.

The adverse morbidity and mortality due to cardiotoxicity in patients treated for cancer has prompted a move for earlier diagnosis of myocardial injury. Current guidelines recommend biomarker screening during cardiotoxic treatment. However, the risk conferred by biomarker elevations in this subgroup

Background: The combination of CDK 4/6 inhibition and endocrine therapy has emerged as the new first line standard of care treatment for patients with hormone receptor (HR) +ve metastatic breast cancer (MBC)1. Ribociclib plus letrozole has been shown to improve PFS (25.3 vs 16.0 months; log-rank P=9.63x10-8) compared to letrozole alone2. More recently, this benefit has also been demonstrated in pre- and peri-menopausal women in combination with ovarian suppression and tamoxifen or an aromatase inhibitor (AI), with an improved overall survival (40.9 months vs OS not reached; HR = 0.712; p=0.00973) in the MONALEESA-7 study3. Approximately 800 patients in Australia participated in the ribociclib medicine access program (MAP) between May 2017 and June 2018, prior to government funding. Beyond eligibility criteria for the program and clinician name, no patient data was initially captured, consistent with usual practice for MAPs, due to the multiple challenges related to ethics, data ownership, security and patient privacy. We have previously demonstrated the feasibility of successful data collection alongside MAPs4 which can yield benefits for clinicians, industry and the broader medical community. Based on this we plan to retrospectively collect data for patients treated as part of the Australian ribociclib MAP. Trial Design: This is a secondary data use, non-interventional study of patients in Australia who received treatment with the combination of an AI and ribociclib, obtained via a MAP, for HR+ HER2- MBC. The target sample size is 250 patients from ~15 sites. De-identified patient data will be retrieved from the patient’s medical records and entered on to an electronic case report form. Data collection is anticipated to commence in July 2019 with the final treatment and survival outcomes collected in late 2020, thus allowing for a minimum of 24 month follow up for all patients from the start date of treatment with ribociclib and AI (May 2017 - June 2018). Study Aims: The primary aim of the study is to describe real world clinical and tumour characteristics of patients with HR+ HER2-ve MBC in Australia who are recommended and received ribociclib in combination with an aromatase inhibitor in the first line setting. Details of adjuvant therapy received and the tolerability of the treatment combination including dose interruptions, dose reductions and significant adverse events of interest related to ribociclib will be assessed. Secondary aims include time to treatment progression and progression free survival for the ribociclib and AI combination, and to explore the disease course post progression, including clinician choice of subsequent lines of therapy in routine clinical practice. References: 1. Cardoso F, Senkus E, Costa A et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Ann Oncol 2018;29:1634-1657. 2. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 2018;29:1541-47. 3. Im SA, Lu YS, Bardia A, et al: Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. June 4, 2019 (early release online) 4. Lok SW, De Boer R, Cordwell C et al. Demonstrating the feasibility of collecting secondary, de-identified data on Australian patients receiving treatment as part of a Medicine Access Program. Intern Med J. 2019 Feb 28. Acknowledgement We thank Novartis for providing funding for this Research Collaboration. Citation Format: Sheau Wen Lok, Sally Baron-Hay, Elgene Lim, Robert Blum, Fran Boyle, Kerrie Clarke, Katharine Cuff, Michael Green, Laeeq Malik, Kelly Mok, Nick Murray, Louise Nott, Michelle Nottage, Ali Tafreshi, Daphne Tsoi, Belinda Yeo, Peter Gibbs, Richard De Boer. A 'real world' experience of CDK4/6 inhibition with ribociclib and endocrine therapy in hormone receptor positive metastatic breast cancer in Australia [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-01.

Aims The IHC4+C score combines assessment of oestrogen receptor (ER), progesterone receptor (PgR), HER2 and Ki67 with clinicopathological parameters to identify the risk of distant disease recurrence in patients with breast cancer, so, aiding treatment decision-making on adjuvant chemotherapy. Despite low cost and wide availability, the reported use of IHC4+C remains limited; one explanation for this is the perception that immunohistochemistry (IHC)-based methods and assessment of them lack precision, reproducibility and portability. We examined the effects of decentralised testing and easily reproducible estimate-based scoring methods on IHC4+C scores to determine its suitability for wider adoption. Methods Sections from a breast cancer tissue micro-array (TMA) were distributed to three centres undertaking diagnostic breast cancer IHC. Centres stained sections using their standard procedures, and returned them for central assessment. The results were compared with those obtained at IHC4+C9s originating hospital (Royal Marsden Hospital (RMH)). In parallel, TMA sections stained at RMH were scored by a variety of simplified non-counting-based methods. The results were compared with those produced using counting. Results There was a high degree of correlation between individual IHC results produced by external centres and those of RMH (r: 0.797–0.982), and between risk of distant recurrence scores derived from them (r: 0.972–0.984). Scoring methods for ER and PgR could be adapted to require less precision without significantly affecting correlation with counted results (r: 0.933 and 0.980, respectively), but correlation between estimating and counting for Ki67 was poorer (r: 0.855). Conclusions IHC4+C is tolerant of variation in staining and scoring methods. Although additional confirmatory comparative studies are required, these data support use of IHC4+C in clinical practice outside RMH.

Background: Most oestrogen receptor (ER)-positive early breast cancer diagnosed today is highly curable with multimodality treatment. Systemic adjuvant treatments including endocrine therapy and chemotherapy have made a significant contribution to the increasing cure rates over the past three decades. However not all women will require chemotherapy. The IHC4+C score is a prognostic tool that integrates four immunohistochemical measures with clinicopathological features to estimate the residual risk of distant recurrence at 10 years in post-menopausal women with ER-positive breast cancer who have received 5 years of endocrine therapy. Retrospective studies indicate that the test can identify a set of women that are at such low risk of recurrence that chemotherapy can be of little benefit. Methods: In this study, 124 patients were prospectively selected from the multidisciplinary team meeting between January 2013 and April 2014 for IHC4+C testing. Adjuvant systemic treatment recommendations by clinicians were recorded without and with the availability of the score in addition to the patient's decision. Results: There was concordance in the MDT's recommendation without and with the availability of the score in 73% of cases. Clinicians recommended chemotherapy or at least its discussion to 74 (59%) patients, which fell to 32 (34%) patients after the IHC4+C score was made available, sparing one in four tested patients a chemotherapy recommendation, along with its toxicity and expense. Conclusion: This decision impact study shows that when used by clinicians in the multidisciplinary team meeting for adjuvant decision-making, a significant proportion of patients are spared chemotherapy recommendations.

Aims 1. To determine the degree to which alterations in immunohistochemical (IHC) staining for ER, PgR, and Ki67 affect IHC4 scores and distant recurrence estimates. 2. To examine the level of scoring precision needed for accurate use of the IHC4 score. Background The IHC4+clinical (C) score combines assessment of protein expression levels of ER, PgR, HER2 and Ki67 with clinicopathological parameters to identify breast cancer patients at low, intermediate or high risk of distant disease recurrence so aiding treatment decision-making (Cuzick J, et al. JCO 2011;29:4273). The score is used in clinical decision making in our hospital (RMH). Our published studies have shown it provides information that improves decision-making on adjuvant chemotherapy in >65% of patients (Barton S, et al. BrJCancer 2012;106:1760; Yeo BJ, et al. AnnalsOncol 2014;25suppl_1:i2). Despite its low cost and wide availability reported use of IHC4+C in other institutions remains limited (Lakhanpal R, et al. JCO 2014;32:abstr2549); one explanation is the perception that IHC-based methods and the assessment of them lack precision, reproducibility and portability. We have examined the effect of decentralized testing and easily reproduced estimate-based scoring methods on the IHC4 score to determine its suitability for wider adoption. Methods A TMA was constructed from 30 breast cancer cases representative of those for which IHC4+C is requested at RMH. Sections were distributed to three centers that undertake diagnostic breast cancer IHC and that use reagents and platforms from Dako, Leica or Ventana who provide most IHC for oncology globally. Centers carried-out staining using their standard procedures and returned slides for central assessment. Results were compared against those obtained at RMH using standardized methods previously described (Barton S, et al. BrJCancer 2012;106:1760), and were used to calculate IHC4+C and 10-year distant recurrence probability (%DRprob) scores. In parallel the TMA slide stained at RMH for ER was scored by a variety of simplified non-counting based methods. Results were compared with those produced by counted H-Score when used to calculate IHC4+C and %DRprob. Results There was a high-degree of correlation between individual IHC results produced by all three external centers and those of RMH, and of the IHC4 and %DRprob scores derived from them (Tables 1 & 2). Scoring method for ER could be adapted to require less precision without significantly affecting IHC4+C and %DRprob results (correlation coefficients range: 0.90 - 0.98). IHC4%DRprob RMHDakoLeicaRMHDakoLeicaDako0.92 0.97 Leica0.890.95 0.980.98 Ventana0.930.960.950.980.980.98 Table 1. Correlation coefficients for all pair-wise comparisons MeanMedian difference RMHDakoLeicaRMH9.9% Dako8.4%1.0% Leica8.9%0.9%0.5% Ventana9.1%0.6%0.5%0.6% Table 2. Showing for each center, the mean %DRprob score and median value obtained when the absolute difference was calculated between matched scores Conclusion The IHC4+C algorithm is tolerant of variation in staining and ER-scoring method used. Although additional comparative studies are required to confirm them, these data support the use of IHC4+C in routine clinical practice outside its institute of origin. Citation Format: Andrew Dodson, Lila Zabaglo, Belinda Yeo, Keith Miller, Ian Smith, Mitch Dowsett. Risk of recurrence estimates with IHC4 are tolerant of variations in staining and scoring [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-10-06.

Women with estrogen receptor (ER)+ early breast cancer (BC) are at continuing risk of relapse up to at least 15 years after diagnosis, despite being on adjuvant endocrine therapy for approximately 5 years. Extended adjuvant endocrine therapy with an aromatase inhibitor (AI) after 5 years of tamoxifen further reduces the risk of recurrence in postmenopausal women. More recently, continuing tamoxifen for 10 years has also been shown to further reduce the risk of recurrence compared with 5 years. There are no direct comparative data on the relative merits of extended tamoxifen compared with an AI; indirect evidence suggests that an AI may have increased efficacy but a greater adverse effect on quality of life. Results are awaited on the need for continuing front-line adjuvant AIs for more than 5 years. The next challenge is to determine which patients will benefit from this long-term treatment. Currently, tumor size, nodal involvement, and gene expression profile as measured by the PAM50 Risk of Recurrence (ROR) score have all been shown to have prognostic significance for late recurrence beyond 5 years.

Current heart team risk assessment using the Society for Thoracic Surgeons (STS) score incorporates a history of cancer as a covariate. However, this has not been validated in patients undergoing transcatheter aortic valve replacement (TAVR). As the survivorship population increases, it is

Background Metastatic breast cancer (MBC) is a heterogeneous disease, whose clinical course and prognosis may be unpredictable, creating significant uncertainty for patients and their families. Heterogeneity is breast cancer subtypes is now well recognized as a potential reason for treatment resistance. Sampling metastatic sites at the point of diagnosis or upon progression, when safe, is recommended to better guide therapy. Purpose This study evaluated patients currently undergoing treatment for MBC in the clinic to determine the clinical and translational significance of a metastatic sample. Methods Patients currently undergoing treatment for MBC at the Olivia Newton John Centre were identified. Data was collected on patient demographics, clinicopathological information, treatment and duration of response. Translational research tissue was collected, with consent, for DNA and RNA analysis. Results Between January 2017 and May 2018 111 patients were identified. The mean age of MBC diagnosis was 60 years (range 30-87), with a mean follow up time of 2.4 years (range 0.8-16). Fifteen patients died during the study period. Sixty-seven (60%) patients were initially treated for early breast cancer (EBC), with a median disease free interval (DFI) 4.7 years. Half (51%) these patients relapsed after five years. At MBC diagnosis, multiple sites of disease were identified including bone, visceral, brain, nodal and skin/chest wall disease. Bone only disease was common (25%), whereas brain disease was rare overall (9%). Metastatic tissue was collected in 67 (60%) patients, where up to four different sites were biopsied. The most commonly biopsied site was bone (n=21), followed by soft tissue (n=20), chest wall/skin disease (n=12), liver (n=9), lung (n=8) and brain (n=8). Serous disease was collected in 16 patients, including pleural, pericardial, ascitic and cerebrospinal fluid. Based on the EBC subtype (n=67), 70% had luminal disease, 19% had Her2 positive disease and 7% had TNBC. However, based on a metastatic biopsy (n=67), only 61% of patients had luminal disease, 21% had HER2 positive, and 18% had TNBC. Paired EBC and MBC samples were available in 48 patients, with significant change in breast cancer subtype demonstrated in 12 of these patients (25%). The most common change was a loss in ER staining, which included 6 patients from ER positive, HER2 negative to TNBC and three patients who became ER negative but remained HER2 positive. Molecular profiling was performed thus far on 8 samples at the single cell and bulk level. These results highlight a large level of inter- and intra-tumoral heterogeneity, and may result in a better understanding of the molecular pathways specifically deregulated in patients at the point of progression. Conclusion In this single institution series of patients with MBC, over half of the cohort underwent at least one metastatic biopsy. Strikingly, a quarter of patients demonstrated a change in their breast cancer subtype, which directly guided subsequent therapy. Metastatic tissue can provide vital information to inform treatment decisions, which may be guided by translational laboratories having access to fresh tissue at the point of metastatic diagnosis or disease progression. Citation Format: Yeo B, Molinaro T, Merino D, Berthelet J, Pouliot N, Fang C, Bell C, Anderson R. The importance of the metastatic biopsy: Clinical and translational relevance in a real world series of patients with metastatic breast cancer [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 PD9-05.

Background Trastuzumab is currently the standard of care in combination with chemotherapy for patients with early and advanced HER2 positive breast cancer. Some patients with advanced disease have long remissions, but published data on the efficacy and safety of long-term trastuzumab are limited. Patients and Methods We have retrospectively assessed efficacy and safety of trastuzumab on all patients with HER2 positive advanced breast cancer, who received first-line trastuzumab-containing therapy between 2001 and 2009 at a single institution, The Royal Marsden Hospital. Patients who received adjuvant trastuzumab were excluded. The primary endpoints of the study were time to disease progression and response duration. Secondary endpoints included overall response rate, overall survival and cardiac toxicity related to maintenance trastuzumab beyond 12 months. An exploratory analysis of factors predicting long disease remission on trastuzumab beyond 12 months was also performed. Results 192 patients with HER2 positive locally advanced/metastatic breast cancer treated with trastuzumab containing therapy as first line treatment were identified. The median age at start of treatment was 52 years. The main site of metastatic disease was visceral in 136 (71%) of patients, and 16 patients (8.5%) with central nervous system (CNS) involvement. 152 (79%) patients received trastuzumab in combination with chemotherapy. 18 patients (9%) received trastuzumab with endocrine therapy only. 22 (11%) patients received trastuzumab alone. The median time to progression was 45. weeks (95% CI: 38 – 52 weeks). The overall response rate (ORR) was 63%, including 14 patients (7%) with CR and 107 patients (56%) with PR. Overall disease control (CR+ PR+ SD for at least 6 months) was achieved in 169 (88%) patients. Patients who received trastuzumab with chemotherapy had superior response rate (71%) to trastuzumab alone or in combination with endocrine therapy (37% and 58% respectively). 125 patients (65%) were on trastuzumab for more than 1 year, 88 (46%) for more than 2 years, 63 (33%) for more than 3 years and 25 (13%) for 5 years or more. The median overall survival was 125 weeks, and 28% still alive at 5 years. At the time of the analysis with a median follow-up 6yrs, 46 patients (24%) were still alive. 23 of these (50%) had stopped trastuzumab after discussion. 38 patients (20%) had CNS relapse on trastuzumab, of which 19 (10%) relapsed in the brain alone. Maintenance trastuzumab therapy was well tolerated. 29 (15%) patients had any grade LV dysfunction during trastuzumab treatment, of which 11 (6%) stopped trastuzumab. No deaths or other serious side effects related to trastuzumab were observed. Conclusion Trastuzumab frequently achieves long term control of metastatic breast cancer with more than 25% of patients alive after 5 years. The optimal duration of therapy remains uncertain. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-15.

Most patients with early breast cancer do not recur after treatment with multimodality therapy. A minority of patients remain at significant risk of relapse and for some, this risk persists up to and beyond 10 years after diagnosis. Decision tools and genomic assays assist in stratifying patients into low and high risk so that adjuvant treatment intensity and its potential toxicities can be limited to those who have the most to gain from them. Definitive treatment for the intermediate risk patients remains uncertain. The four main breast cancer subtypes show distinct patterns and timing of recurrence although these may change over time as better adjuvant systemic and targeted agents begin to change the natural history of recurrent breast cancer.

Summary points Breast cancer remained the most common cancer in women in 2013 and its incidence continues to rise.1 Nonetheless, mortality is falling, partly as a result of earlier diagnosis through mammographic screening,2 improved surgical techniques and attention to margins, improved delivery of radiotherapy, and better adjuvant medical therapies (fig 1⇓). Despite these improvements, breast cancer remains the second most common cause of death from cancer in women. Fig 1 Incidence of breast cancer in women and mortality rates in the United Kingdom over the past 30 years. Data from Cancer Research UK1 This review focuses on the medical treatment of breast cancer in the adjuvant and metastatic settings, with particular attention to recent advances and changes in practice since our last review in 2008.3 4 We discuss how targeted therapies can be used to individualise and tailor the management of breast cancer according to tumour biology and molecular subtype. #### Sources and selection criteria We used PubMed to identify recent published updates on the medical management of breast cancer. We also referenced presentations from international conferences and consulted with other experts in the breast cancer field. ### Diagnosis Guidelines on the diagnosis of early breast cancer have changed little since our last review. Population based mammography screening for asymptomatic women is currently …

Adjuvant endocrine therapy has made a significant impact in improving overall survival for women with hormone receptor (HR)-positive breast cancer. The anti-estrogen tamoxifen is the most widely used therapy, although in post-menopausal women, aromatase inhibitors (AIs) have further improved outcomes either as an alternative to tamoxifen for 5 years, or given in sequential fashion following initial tamoxifen therapy. However, late recurrence remains perhaps the biggest risk in HR-positive breast cancer, with more than half all recurrences occurring beyond 5 years since primary diagnosis. As such, the current debate is whether extended AI or prolonged tamoxifen therapy should be given, and if so, to whom. We review some of the recent studies that have addressed this question and demonstrated further reduction in risk of recurrence, and discuss the clinical issues that face women and their health care providers in determining who should use which drug, and for how long.

Background: There is great interest in the mutational landscape of metastatic breast cancer (BC) for personalised medicine. Knowledge about how this landscape differs in recurrent lesions from primary BC as a result of metastatic selection or the impact of treatment will extend our knowledge of mechanisms of endocrine resistance and determine the manner in which diagnostics and treatment are integrated. A small number of limited series have reported an increased presence of ESR1 mutations in metastatic lesions after endocrine treatments including aromatase inhibitors (AIs) which are the most common agents for ER+ postmenopausal BC. Aim: To determine the change in mutational profile of 16 genes affected by driver mutations in patients with metastatic BC at the time of progression after an AI. Methods: We conducted targeted sequencing with a custom AmpliSeq panel in 48 matched pairs of FFPE archival blocks of pre-treatment diagnostic and recurrent lesions. 24 of these were metastatic, 24 local recurrences. The genes were AKT1, BRAF, CDH1, ERBB2, ESR1, GATA3, KIT, KRAS, MAP2K4, MAP3K1, PIC3CA, PIK3R1, PTEN, RUNX, SF3B1 and TP53. Only mutations with high depth (>250x) were retained. Germline mutations were identified by 1000 Genomes Project data. C:G>T:A transitions with low frequency ( Results: Median coverage was 782-fold. Good quality data was available on 42 pairs. At least one mutation was found in 34 pairs. Three cases had lost IHC expression of ER in the recurrence. A total of 115 mutations in coding regions or splice sites were identified, the largest number in PIK3CA (in 20 samples), CHD1 (18), MAP3K1 (12), TP53 (12) and PTEN (9). In 47 instances the mutation was private to one or other sample. There was no difference in the number of mutations between the presentation and recurrent lesions. Six ESR1 mutations were found, all private to 5 recurrent lesions (all IHC ER+). Four of these mutations have been previously reported (2x E380Q, 2x D538G), one was novel (D484G) and also in the ligand-binding domain. One had an additional previously reported mutation (H524L). Four of these lesions were metastatic but one in a local recurrence suggesting that the metastatic process is more likely, but not essential in selecting the emergence of ESR1 mutations. HER2 mutations were identified in 3 patients; in two cases private in the presentation tumour while in the other case the mutation in the recurrent lesion (L755S) differed from that in the primary. L755S has been reported to be sensitive to neratinib in experimental systems. CDH1 (e-cadherin) mutations were numerically higher than reported in other series. The mutations were across the gene and private in 4 pretreatment and 2 recurrent lesions (6 had identical mutations). They were not associated with lobular phenotype. Conclusions: These data confirm that recurrences after AI but not primary ER+ tumours often contain ESR1 mutations that could influence clinical decision making. The high number of CDH1 mutations at diagnosis may be at least in part because of the selection of recurrent ER+ cases. The data stress the individuality of mutational profiles in recurrent BC and the need for individual interpretation of the data. Citation Format: Gellert P, Ribas R, Pancholi S, Lopez-Knowles E, Yeo B, Garcia-Murillas I, Pearson A, Smith I, Turner N, Dowsett M, Martin L-A. Occurrence of natural ESR1 mutations during acquisition of endocrine resistance in breast cancers and widely used ER+ cell lines. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-02.

e12004 Background: Eribulin mesylate (EM) is a non-taxane, microtubule dynamic inhibitor that has been approved for the treatment of patients with metastatic breast cancer (MBC) after the pivotal p...

There is increasing interest in the use of non-toxic natural products for the treatment of various pathologies, including cancer. In particular, biologically active constituents of the ginger oleoresin (Zingiber officinale Roscoe) have been shown to mediate anti-tumour activity and to contribute to the anti-inflammatory, antioxidant, antimicrobial, and antiemetic properties of ginger. Here we report on the inhibitory properties of [10]-gingerol against metastatic triple negative breast cancer (TNBC) in vitro and in vivo. We show that [10]-gingerol concentration-dependently induces apoptotic death in mouse and human TNBC cell lines in vitro. In addition, [10]-gingerol is well tolerated in vivo, induces a marked increase in caspase-3 activation and inhibits orthotopic tumour growth in a syngeneic mouse model of spontaneous breast cancer metastasis. Importantly, using both spontaneous and experimental metastasis assays, we show for the first time that [10]-gingerol significantly inhibits metastasis to multiple organs including lung, bone and brain. Remarkably, inhibition of brain metastasis was observed even when treatment was initiated after surgical removal of the primary tumour. Taken together, these results indicate that [10]-gingerol may be a safe and useful complementary therapy for the treatment of metastatic breast cancer and warrant further investigation of its efficacy, either alone or in combination with standard systemic therapies, in pre-clinical models of metastatic breast cancer and in patients.