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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.

Background Several thousand breast cancer patients develop resistance to aromatase inhibitors (AIs) each year in the UK. Rational treatment requires an improved molecular characterisation of resistant disease. Materials and methods The mutational landscape of 198 regions in 16 key breast cancer genes and RNA expression of 209 genes covering key pathways was evaluated in paired biopsies before AI treatment and at progression on AI from 48 patients. Validity of findings was assessed in another five ESR1-mutated tumours progressing on AI. Results Eighty-nine mutations were identified in 41 matched pairs (PIK3CA in 27%; CDH1 in 20%). ESR1 (n = 5), ERBB2 (n = 1) and MAP2K4 (n = 1) had mutations in the secondary sample only. There was very high heterogeneity in gene expression between AI-resistant tumours with few patterns apparent. However, in the ESR1-mutated AI-resistant tumours, expression of four classical oestrogen-regulated genes (ERGs) was sevenfold higher than in ESR1 wild-type tumours, a finding confirmed in the second set of ESR1-mutated tumours. In ESR1 wild-type AI-resistant tumours ERG expression remained suppressed and was uncoupled from the recovery seen in proliferation. Conclusions Major genotypic and phenotypic heterogeneity exists between AI-resistant disease. ESR1 mutations appear to drive oestrogen-regulated processes in resistant tumours.

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.

The human eye can distinguish as many as 10,000 different colours but is far less sensitive to variations in intensity

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.

Neoadjuvant endocrine treatment has become of increasing interest for downstaging primary ER+ breast cancers as it has become clear that the pathologic complete response rate of luminal tumours to chemotherapy is much lower than that of non-luminal and differs little from that to endocrine therapy. There is much more experience in postmenopausal than premenopausal women. Aromatase inhibitors are generally the agent of choice. Responses are lower in those with the low levels of ER. While duration of endocrine treatment in clinical trials has usually been standardized at around three to four months it is clear that volume reductions continue to occur beyond that time in a large proportion of cases and routine clinical practice is often to treat to maximum response. This relatively slow emergence of downstaging relates to the absence of any increase in apoptosis with endocrine therapy and dependence of responses on the antiproliferative effects of oestrogen withdrawal: apoptosis occurs but at a slightly lower rate such that cell loss is attritional. The dependence of responses on the reduced proliferation underpins the value of Ki67 as an intermediate end-point for treatment benefit with multiple studies having found that relative effects on proliferation by different drugs in neoadjuvant trials match their relative impact on recurrence. While change in Ki67 is now accepted as a validated endpoint for comparing endocrine agents in the neoadjuvant scenario, on-treatment levels of Ki67 are related to long-term prognosis more closely than pretreatment Ki67. The Preoperative Endocrine Prognostic Index (PEPI) that combines residual Ki67 score with measures of on-treatment ER and other clinicopathologic factors has also found application in clinical trials. The potential to make longitudinal assessments of both clinical and biomarker responses has encouraged the development of novel clinical trial designs for assessing the impact of agents that aim to enhance response beyond that of endocrine agents alone. Such strategies include the early measurement of residual Ki67 levels after challenge with an endocrine agent alone and evaluation of the impact of the added agent on Ki67 or other agent-specific end-points.

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.