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Clinico-pathologic characteristics of patients according to NGS results (success/failure).

Weighted Kaplan-Meier (KM) estimates of breast cancer-free interval (BCFI) and distant recurrence-free interval (DRFI) according to tumor subtype, separately by PIK3CA mutational status (mutated, MUT vs wild-type, WT). The 5-year event-free estimates (95% CI) are provided. Hazard ratio (HR) estimates (95% CI) and log-rank tests from weighted univariate models.

Purpose:Women with hormone receptor–positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk.Experimental Design:In a secondary analysis of Study of Letrozole Extension trial, a case-cohort–like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models.Results:Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). PIK3CA mutations and MYC CNGs were associated with lower (P = 0.03) and higher (P = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with CCND1, ERBB2, and MYC CNGs (P = 0.01, P < 0.001, and P = 0.03, respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48–6.92; P = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61–7.75; P = 0.002) and in multivariable models adjusted for clinicopathologic factors.Conclusions:Postmenopausal women with hormone receptor–positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.

Purpose:Women with hormone receptor–positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk.Experimental Design:In a secondary analysis of Study of Letrozole Extension trial, a case-cohort–like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models.Results:Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). PIK3CA mutations and MYC CNGs were associated with lower (P = 0.03) and higher (P = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with CCND1, ERBB2, and MYC CNGs (P = 0.01, P < 0.001, and P = 0.03, respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48–6.92; P = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61–7.75; P = 0.002) and in multivariable models adjusted for clinicopathologic factors.Conclusions:Postmenopausal women with hormone receptor–positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.

Background: In animal models of hormone receptor positive (HR+) breast cancer, acquired resistance to continued letrozole was shown to be reversed by estrogen-induced apoptosis. We hypothesized that the rise in estrogen levels during short treatment interruptions would resensitize breast cancer cells to letrozole and improve treatment outcome. SOLE tested the hypothesis that 3 mos treatment-free intervals during extended adjuvant therapy will improve disease-free survival (DFS). We previously reported the primary endpoint after 60 mos median follow-up: extended intermittent letrozole did not improve DFS vs extended continuous letrozole. However, only 9% of pts had breast cancer events, justifying updating the analysis with longer follow-up. The dynamic of recovery of estrogen levels after stopping letrozole therapy has not been previously reported. Methods: SOLE enrolled 4884 postmenopausal women with HR+ lymph node-positive BC who had completed 4-6 yrs of adjuvant endocrine therapy (19% SERM, 43% AI, 38% both; stratification factor). Pts were randomized to an additional 5 yrs continuous letrozole (2.5 mg daily; n=2441) vs 5 yrs intermittent letrozole (taken for the first 9 mos of yrs 1-4, and 12 mos in yr 5; n=2443). We report the final analysis of the SOLE trial after 84 mos median follow-up. In SOLE-EST, levels of estradiol (E2), estrone (E1) and estrone sulphate (E1S) at 0, 9, 10.5 and 12 mos after randomization were determined using a highly sensitive assay in a subgroup of 90 evaluable patients (21 in the continuous and 69 in the intermittent group). Results: There were 923 DFS events. 7 yr DFS was 81.5% in both groups. More pts had distant metastases in the continuous group (8.7% vs 7.5%) while second (non-breast) malignancies were more frequent in the intermittent group (5.5% vs 4.7%). Similar outcomes were observed for breast cancer-free interval (BCFI) (88.6% vs 88.0%), distant recurrence-free interval (DRFI) (91.6% vs 90.4%), and overall survival (OS) (90.6% vs 89.6%) for pts assigned intermittent vs continuous letrozole. In the intermittent group, median E2, E1 and E1S levels more than doubled compared with levels at 9 mos after randomization in the first 6 weeks after stopping letrozole during the treatment free interval while levels were stable for the 21 pts tested in the continuous group. Conclusions: Among postmenopausal women with HR+ BC, extended intermittent letrozole did not improve DFS vs continuous letrozole. Similar outcome was consistently observed for BCFI, DRFI and OS. The SOLE-EST substudy indicates an important increase in estrogen levels as soon as 6 weeks after stopping letrozole therapy in the intermittent group. Further investigation of prior exposure to aromatase inhibitors in relation with outcome and with E2, E1 and E1S levels in SOLE-EST are underway. Citation Format: Guy Jerusalem, Subrina Farah, Jacquie Chirgwin, Stefan Aebi, Per Karlsson, Patrick Neven, Erika Hitre, Marie-Pascale Graas, Edda Simoncini, Claus Kamby, Alastair Thompson, Sibylle Loibl, Joaquín Gavilá, Katsumasa Kuroi, Christian Marth, Bettina Müller, Seamus O'Reilly, Andrea Gombos, Thomas Ruhstaller, Harold Burstein, Manuela Rabaglio, Barbara Ruepp, Giuseppe Viale, Richard D Gelber, Alan S Coates, Angelo Di Leo, Aron Goldhirsch, Meredith Regan, Marco Colleoni. SOLE (study of letrozole extension), a phase 3 randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph node-positive, early breast cancer (BC): Final analysis and sole estrogen substudy (SOLE-EST) [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 P5-12-01.

PURPOSE Sexual dysfunction is an important concern of premenopausal women with early breast cancer. We investigated predictors of sexual problems in two randomized controlled trials. METHODS A subset of patients enrolled in TEXT and SOFT completed global and symptom-specific quality-of-life indicators, CES-Depression and MOS-Sexual Problems measures at baseline, six, 12 and 24 months. Mixed models tested the association of changes in treatment-induced symptoms (baseline to 6 months), depression at 6 months, and age at randomization with changes in sexual problems over 2 years. RESULTS Sexual problems increased by 6 months and persisted at this level. Overall, patients with more severe worsening of vaginal dryness, sleep disturbances and bone or joint pain at 6 months reported a greater increase in sexual problems at all time-points. Depression scores were significantly associated with sexual problems in the short-term. All other symptoms had a smaller impact on sexual problems. Age was not associated with sexual problems at any time-point. CONCLUSION Among several key symptoms, vaginal dryness, sleep disturbance, and bone and joint pain significantly predicted sexual problems during the first 2 years. Early identification of these symptoms may contribute to timely and tailored interventions.

Objectives Industry-supported decision impact studies demonstrate that Oncotype Dx (ODX) changes treatment recommendations (TR) in 24-40% of hormone receptor+/HER2- patients. ODX is not reimbursed by third-party payers in Australia, potentially resulting in more selective use. We sought to evaluate the impact of self-funded ODX on TRs. Methods Data collected included demographics, tumor characteristics, indication for ODX and pre- and post-recurrence score (RS) TR. Primary endpoint was frequency of TR change and associations with TR change were sought. Results Eighteen physicians contributed 382 patients (median age 54). A total of 232 (61%) of tumors were T1 and were grade 1, 2 and 3 in 49 (13%), 252 (66%) and 79 (21%). A total of 257 (67%) were node negative. Assay indications were: confirm need for chemotherapy (CT) (36%), confirm omission of CT (40%) and genuine equipoise (24%). RS was low (≤17) in 55%, intermediate (18-31) in 36% and high (≥32) in 9%. Thirty-eight percent of patients had TR change post-ODX. Sixty-five percent of patients recommended CT pre-ODX changed to hormone therapy alone (HT)-more likely if lower grade and if ER and/or PR > 10%. Fourteen percent of patients with pre-ODX TR for HT added CT-more likely if ER and/or PR ≤10% and if Ki67 > 15% Overall, TR for CT decreased from 47% to 24%. Conclusion Patient-funded ODX changed TRs in 38% of patients, de-escalating 65% from CT to HT and adding CT to 14% of those recommended HT. These changes were greater than an industry-funded study suggesting that physicians can identify situations where the assay may influence decisions.

Background Informal caregivers provide extended support to people with cancer but they receive little support from the health care system to assist them in their caring role. The aim of this single-blind, multi-centre, randomised controlled trial was to test the efficacy of a telephone outcall program to reduce caregiver burden and unmet needs, and improve psychological well-being among cancer caregivers, as well as evaluating the potential impact on patient outcomes. Methods Cancer patient/caregiver dyads (N = 216) were randomised to a telephone outcall program (n = 108) or attention control group (n = 108). The primary outcome was self-reported caregiver burden. Secondary endpoints included depressive symptoms, unmet needs, self-esteem, self-empowerment, and health literacy. Data were collected at baseline and at both 1 and 6 months post-intervention. An intention to treat analysis was performed. Results The intervention had no effect on the primary outcome (caregiver burden), but reduced the number of caregiver unmet needs (intervention group baseline, mean = 2.66, 95% confidence interval (CI) [1.91–3.54]; intervention group 1 month post intervention, mean = 0.85, 95%CI [0.42–1.44]; control group baseline, mean = 1.30 95%CI [0.80–1.94], control group 1 month post intervention, mean = 1.02 95%CI [0.52–1.69]; p = 0.023). For caregivers at risk for depression, the intervention had a significant effect on caregivers’ confidence in having sufficient information to manage their health (p = 0.040). No effects were found for patients’ depressive symptoms, unmet needs, self-empowerment, and other health literacy domains. Conclusions While caregiver burden was not reduced, the outcall program was effective in reducing unmet needs in caregivers. Provision of cancer information and support via a telephone service may represent a feasible approach to reducing unmet needs among cancer caregiver populations. Trial registration ACTRN12613000731796; prospectively registered on 02/07/2013. Electronic supplementary material The online version of this article (10.1186/s12885-017-3961-6) contains supplementary material, which is available to authorized users.

Background: In premenopausal women with breast cancer any treatment that causes abrupt, premature ovarian failure increases the risk of sexual problems. Randomized-controlled trials in this population reported a worsening in sexual functioning over time irrespective of adjuvant endocrine treatment. We investigated key symptoms related to endocrine therapy, depression and age as predictors of sexual problems in premenopausal women with early breast cancer treated in the IBCSG TEXT/SOFT trials over the first two years of endocrine therapy. Methods: A subset of patients (pts) enrolled by centers with English as primary language to TEXT (1027 of 2672 pts) and SOFT (1260 of 3066 pts) completed a questionnaire consisting of global and symptom-specific quality of life indicators, the CES-Depression (CES-D) and the MOS- Sexual Problems (MOS-SP) measures at baseline, 6, 12 and 24 months. The analysis considered 5 cohorts of pts according to chemotherapy use (yes/no), trial (SOFT/TEXT) and endocrine treatment assignment (tamoxifen alone [T], T or exemestane [E] with ovarian function suppression [OFS]). Mixed modeling was used to test the effect of the following on changes in sexual problems (MOS-SP total score) over two years: changes in treatment-induced symptoms (hot flushes, vaginal dryness, sleep disturbances, bone/joint pain, troubled by weight gain, tiredness, nausea/vomiting) from baseline to 6 months; depression at 6 months; and age at randomization. The model included severity groups of symptoms, depression (all dichotomized by median) and age (< 40 vs ≥40 years), 5 cohorts, time points (6, 12, 24 months), baseline covariates, and interactions of symptoms, timepoints and cohorts. Results: Overall across cohorts, pts with more severe worsening of vaginal dryness and sleep disturbances at 6 months reported a greater increase in sexual problems at all timepoints (p Conclusion: Among several key symptoms related to endocrine therapy, only vaginal dryness and sleep disturbances significantly predicted sexual problems during the first two years in pts who received adjuvant endocrine therapy with or without chemotherapy. Depression predicted sexual problems only in the cohort of pts who received combined endocrine treatment without chemotherapy. Early identification of vaginal dryness, sleep disturbances and depression is important for timely and tailored interventions. Citation Format: Ribi K, Luo W, Burstein HJ, Naughton MJ, Chirgwin J, Ansari RH, Walley BA, Salim M, van der Westhuizen A, Abdi E, Francis PA, Budman DR, Kennecke H, Harvey VJ, Giobbie-Hurder A, Fleming GF, Pagani O, Regan MM, Bernhard J. The effects of treatment-induced symptoms, depression and age on sexuality in premenopausal women with early breast cancer receiving adjuvant endocrine therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-09.

Purpose To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer. Patients and Methods International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor– and progesterone receptor–negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths. Results After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06;P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%). Conclusion CM maintenance did not produce a significant reduction in DFS events in hormone receptor–negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.

Background: An Australian industry-funded decision impact study demonstrated that Oncotype Dx (ODX) changed treatment recommendations (TR) in 24% of hormone receptor+/HER2- patients. ODX is available in Australia, but is self-funded by patients (∼USD 4175), so its use is limited. We sought to evaluate the impact of self-funded ODX on TRs. A high proportion of TR changes would imply a benefit to the broader community if ODX testing were available to all appropriately selected patients. Methods: All Australian physicians who had ordered >5 ODX were invited to participate. Data collected included demographics, tumor characteristics, indication for ODX (confirm need for chemotherapy (CT), confirm omission of CT, or genuine equipoise). Pre- and post Recurrence Score (RS) TRs (CT recommended versus hormone therapy alone (HT)) were also collected. The primary endpoint was the frequency and predictors of TR change. Relationships between categorical variables were assessed using Chi2 test and logistic regression analysis determined factors associated with TR change post-ODX. Results: 382 patients with median age 54 (range 31-76) were included. 18 physicians contributed a median of 17 (5-87) patients. Tumor characteristics were: T1 232 (61%); ≥T2 150 (39%); grade 1 49 (13%), grade 2 252 (66%) and grade 3 79 (21%) and Ki67>15% in 131/231 (49%). 257 (67%) were node negative (N0). Assay indications were: confirm need for CT in 36%, confirm omission of CT in 40% and genuine equipoise in 24%. RS was low in 55%, intermediate in 36% and high in 9%. Of 355 patients with a TR recorded pre-ODX, 38% had TR change post-ODX. 109/168 patients (65%) recommended CT pre-ODX changed to HT alone, and this was more likely if lower grade (82.1% vs 50.8% p15% (27.5% vs 9.8% p=0.015). Overall, TR for CT decreased from 47% to 24%. Influence of adverse prognostic factors (defined as ≥T2, grade 3, ER and/or PR Number of "adverse factors"01234N0 (n=234)Number of patients90116244 RS median (range)16 (0-40)17 (0-41)26 (5-52)31 (22-40) TR change19/90 (21%)45/116 (39%)6/24 (25%)2/4 HT to CT7/71 (10%)10/61 (16%)2/11 (18%)1/2 CT to HT12/19 (63%)35/55 (64%)4/13 (31%)1/2 N+ (n=114)Number of patients22424181 RS median (range)14 (5-34)16 (0-38)14 (0-32)24 (12-50)39 TR change11/22 (50%)21/42 (50%)25/41 (42%)3/8 (38%)0/1 HT to CT3/13 (23%)3/14 (21%)0/12NANA CT to HT8/9 (89%)18/28 (64%)25/29 (86%)3/7 (43%)0/1 Conclusions: Patient self-funded ODX changed TRs in 38%. 65% who would have been recommended CT pre-ODX were spared CT post-ODX, suggesting that traditional histopathological indications for CT in ER+ patients has led to many receiving CT unnecessarily. Where the pre ODX TR was HT alone, only 14% changed to adding CT, suggesting that the indication was reassurance that CT could be omitted. Consideration could be made for third party funding in select patient groups. Citation Format: Chin-Lenn L, Segelov E, De Boer R, Marx G, Hughes TM, McCarthy N, White S, Foo S, Rutovitz J, Della Fiorentina S, Jennens R, Antill Y, Tsoi D, Cronk M, Lombard J, Kiely BE, Chirgwin J, Gorelik A, Mann GB. Indications for, and impact of oncotype DX on adjuvant treatment recommendations when third party funding is unavailable. [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 P5-15-02.

In the phase III SOLE trial, the extended use of intermittent versus continuous letrozole for 5 years did not improve disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Intermittent therapy with 3-month breaks may be beneficial for patients’ quality of life (QoL). In the SOLE QoL sub-study, 956 patients completed the Breast Cancer Prevention Trial (BCPT) symptom and further QoL scales up to 24 months after randomisation. Differences in change of QoL from baseline between the two administration schedules were tested at 12 and 24 months using repeated measures mixed-models. The primary outcome was change in hot flushes at 12 months. There was no difference in hot flushes at 12 months between the two schedules, but patients receiving intermittent letrozole reported significantly more improvement at 24 months. They also indicated less worsening in vaginal problems, musculoskeletal pain, sleep disturbance, physical well-being and mood at 12 months. Overall, 25–30% of patients reported a clinically relevant worsening in key symptoms and global QoL. Less symptom worsening was observed during the first year of extended treatment with the intermittent administration. For women experiencing an increased symptom burden of extended adjuvant endocrine therapy, an intermittent administration is a safe alternative. Clinical trial information: NCT00553410.

BACKGROUND: In the phase III SOLE trial, the extended use of intermittent versus continuous letrozole for 5 years did not improve disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Intermittent therapy with 3-month breaks may be beneficial for patients' quality of life (QoL). METHODS: In the SOLE QoL sub-study, 956 patients completed the Breast Cancer Prevention Trial (BCPT) symptom and further QoL scales up to 24 months after randomisation. Differences in change of QoL from baseline between the two administration schedules were tested at 12 and 24 months using repeated measures mixed-models. The primary outcome was change in hot flushes at 12 months. RESULTS: There was no difference in hot flushes at 12 months between the two schedules, but patients receiving intermittent letrozole reported significantly more improvement at 24 months. They also indicated less worsening in vaginal problems, musculoskeletal pain, sleep disturbance, physical well-being and mood at 12 months. Overall, 25-30% of patients reported a clinically relevant worsening in key symptoms and global QoL. CONCLUSION: Less symptom worsening was observed during the first year of extended treatment with the intermittent administration. For women experiencing an increased symptom burden of extended adjuvant endocrine therapy, an intermittent administration is a safe alternative. CLINICAL TRIAL INFORMATION: Clinical trial information: NCT00651456. ispartof: BRITISH JOURNAL OF CANCER vol:120 issue:10 pages:959-967 ispartof: location:England status: published

Background: AIMSS is experienced by approximately half of women taking an aromatase inhibitor (AI), impairing quality of life and in some leading to AI discontinuation. There is a lack of evidence for effective AIMSS treatments. Aim: To investigate the importance of AIMSS in Australian women with early breast cancer. Method: A survey invitation was distributed to 2390 members of the BCNA Review and Survey Group in April 2014. The online questionnaire consisted of 45 questions covering demographics, AI use, clinical manifestations and risk factors for AIMSS, reasons for AI discontinuation and efficacy of interventions used for AIMSS. AIMSS was defined as joint pain or stiffness that developed or worsened after commencing an AI. Results: Of 594 respondents, 370 (62%) were eligible. Reasons for exclusion were: preinvasive disease, locally advanced/metastatic breast cancer, or other reason. Eligible respondents had a median age range of 50-59 years. Duration of AI use varied (26%1year, 64% 1-5years, 10% 5years). 57% had received adjuvant chemotherapy. 43% of these commenced AI within 3 months of chemotherapy and 30% within 3-6 months of chemotherapy. A vitamin D test was performed in 64% of women and 68% were currently using vitamin D supplements. Joint pain during menopause was reported by 22% of respondents. AIMSS occurred in 302/370 women (81%). Of those who developed AIMSS, sites affected were feet (68%), hands or wrists (65%), knees (62%), hips (56%), shoulders or elbows (49%), back (46%), or neck (3%). 34% of women had considered stopping an AI because of AIMSS. 99 (27%) of respondents had discontinued AI for any reason and of these 68% discontinued because of AIMSS. Non-AIMSS symptoms identified as reasons for discontinuation included fatigue, vaginal/urinary symptoms and hot flushes. In respondents who discontinued AI, 20% ceased use in the first 3 months, 30% during months 3-12 and 38%12 months. 42% of respondents who discontinued an AI restarted the same or a different AI after a treatment break. To manage AIMSS 23% of respondents used doctor prescribed medications (eg anti-inflammatories, codeine, morphine,), 55% over the counter (OTC) or complementary medicines (eg low dose anti-inflammatories, paracetamol, chondroitin, fish or krill oil, glucosamine, and vitamin D) and 29% alternative therapies (eg acupuncture, massage, Tai Chi and yoga). Respondents identified the following in each of the above categories as most successful in relieving AIMSS symptoms: doctor prescribed anti-inflammatories, paracetamol and yoga. Doctor prescribed medications and OTC/complementary medicine either completely or significantly relieved AIMSS in 12% and 25% of cases respectively. 27% of respondents found that one or more of the interventions that they had used to manage AIMSS helped prevent AI discontinuation. Conclusion: AIMSS is a significant issue for Australian women and is an important reason for AI discontinuation. Women use a number of interventions to manage AIMSS, however their efficacy appears limited. Effective AIMSS interventions are needed, to improve quality of life and reduce AI discontinuation. Citation Format: Janine M Lombard, Nicholas Zdenkowski, Kathy Wells, Nicca Grant, Linda Reaby, John F Forbes, Jacquie Chirgwin. Aromatase inhibitor induced musculoskeletal syndrome (AIMSS) in Australian women with early breast cancer: An Australia and New Zealand Breast Cancer Trials Group (ANZBCTG) survey of members of the Breast Cancer Network Australia (BCNA) [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 P1-12-05.

Caregivers play a vital role in caring for people diagnosed with cancer. However, little is understood about caregivers' capacity to find, understand, appraise and use information to improve health outcomes. The study aimed to develop a conceptual model that describes the elements of cancer caregiver health literacy. Six concept mapping workshops were conducted with 13 caregivers, 13 people with cancer and 11 healthcare providers/policymakers. An iterative, mixed methods approach was used to analyse and synthesise workshop data and to generate the conceptual model. Six major themes and 17 subthemes were identified from 279 statements generated by participants during concept mapping workshops. Major themes included: access to information, understanding of information, relationship with healthcare providers, relationship with the care recipient, managing challenges of caregiving and support systems. The study extends conceptualisations of health literacy by identifying factors specific to caregiving within the cancer context. The findings demonstrate that caregiver health literacy is multidimensional, includes a broad range of individual and interpersonal elements, and is influenced by broader healthcare system and community factors. These results provide guidance for the development of: caregiver health literacy measurement tools; strategies for improving health service delivery, and; interventions to improve caregiver health literacy.

Aim We aimed to systematically review and summarize data from the available clinical trials that examined the treatment of HER2-positive metastatic breast cancer. Methods We reviewed phase 2 and 3 studies in which an anti-HER2 agent was used in one or both arms of the study. While formal meta-analysis was not possible for such a heterogeneous group of trials, resulting forest plots outline some generalizable findings. Results There is strong evidence that the addition of an anti-HER2 agent to standard chemo- or endocrine therapy improves clinically relevant measurable outcomes. There is also consistent evidence that initial treatment with trastuzumab alone (and subsequent use of a cytotoxic) is inferior to the initial combination of trastuzumab plus chemotherapy, and that either T-DM1 or dual anti-HER2 agents are superior to single anti-HER2 agent regimens. There is no strong evidence that the use of more than one cytotoxic agent together with an anti-HER2 agent confers any benefit over a single cytotoxic, anti-HER2 combination. Conclusion This review provides a strong evidence base for current clinical practice with a discussion of treatment in the Australian setting.

Improvements in the treatment of metastatic HER2-positive breast cancer constitute one of the great advances in breast cancer medicine of the last generation. From being a highly aggressive fatal condition, the use of anti-HER2-targeted therapies, in particular trastuzumab, has led to significant improvements in disease outcomes. There are reports of increasing numbers of patients alive and well more than 5 years from diagnosis of metastatic disease. Nevertheless, there remain many complex and clinically difficult scenarios where there is little in the way of randomized evidence or published guidelines to guide decision making. As a companion piece to our review of HER2-targeted therapies in the metastatic setting, we decided to focus on a series of clinical scenarios that fell outside of the standard trial-based settings and where opinions and guidance from experienced clinicians and experts in the field would be considered useful to help develop safe and effective treatment strategies. The following eight cases were put forward by our panel of experts, voted on by their peers to select the most relevant and interesting cases, and the discussions worked on by teams of two followed by review and commentary by another team of two.

Background Neoadjuvant chemotherapy has a sound rationale for use in women with large operable breast cancer, and achievement of pathological complete response (pCR) is prognostic. Epirubicin and cyclophosphamide followed by docetaxel is a standard chemotherapy regimen for early breast cancer. In metastatic breast cancer the combination of gemcitabine and a taxane has shown promising results. This phase II study investigated the efficacy and safety of incorporating gemcitabine into neoadjuvant therapy. Methods Female patients with operable breast cancer that was clinically T2 (≥3 cm) or T3-4, N0-1, M0 were enrolled to receive 24 weeks of neoadjuvant chemotherapy using epirubicin and cyclophosphamide followed by docetaxel and gemcitabine, plus trastuzumab if HER2-positive. The primary endpoint was the pathological complete response (pCR) rate in the breast in separate HER2-negative and HER2-positive cohorts. Secondary endpoints included pCR in both the breast and axillary lymph nodes, clinical and radiological response rates, disease free survival and safety. Results 81 patients were enrolled: 63 HER2-negative and 18 HER2-positive. 67 (84%) completed all cycles of chemotherapy, and 78 (96%) proceeded to surgery. pCR was achieved by 12 (20%) patients with HER2-negative, and 9 (53%) with HER2-positive disease. At the first interim analysis, addition of prophylactic G-CSF was recommended due to excess neutropenia. The HER2-negative cohort was closed to accrual because it did not meet the pre-specified target for pCR, and the HER2-positive cohort was closed due to slow accrual. At a median follow-up of 24 months, 12 of 81 (15%) patients had experienced a relapse of their breast cancer. Conclusion Neoadjuvant gemcitabine, when added to docetaxel, after epirubicin and cyclophosphamide, did not reach the pre-specified expectations for pCR rate in HER2-negative tumours. Excess neutropenia was observed, requiring growth factor support. Addition of gemcitabine to docetaxel in this schedule cannot be recommended. Australia and New Zealand Clinical Trials Registry ( www.anzctr.org.au ) registration number ACTRN12606000191594 .

Purpose To investigate adherence to endocrine treatment and its relationship with disease-free survival (DFS) in the Breast International Group (BIG) 1-98 clinical trial. Methods The BIG 1-98 trial is a double-blind trial that randomly assigned 6,193 postmenopausal women with hormone receptor–positive early breast cancer in the four-arm option to 5 years of tamoxifen (Tam), letrozole (Let), or the agents in sequence (Let-Tam, Tam-Let). This analysis included 6,144 women who received at least one dose of study treatment. Conditional landmark analyses and marginal structural Cox proportional hazards models were used to evaluate the relationship between DFS and treatment adherence (persistence [duration] and compliance with dosage). Competing risks regression was used to assess demographic, disease, and treatment characteristics of the women who stopped treatment early because of adverse events. Results Both aspects of low adherence (early cessation of letrozole and a compliance score of < 90%) were associated with reduced DFS (multivariable model hazard ratio, 1.45; 95% CI, 1.09 to 1.93; P = .01; and multivariable model hazard ratio, 1.61; 95% CI, 1.08 to 2.38; P = .02, respectively). Sequential treatments were associated with higher rates of nonpersistence (Tam-Let, 20.8%; Let-Tam, 20.3%; Tam 16.9%; Let 17.6%). Adverse events were the reason for most trial treatment early discontinuations (82.7%). Apart from sequential treatment assignment, reduced adherence was associated with older age, smoking, node negativity, or prior thromboembolic event. Conclusion Both persistence and compliance are associated with DFS. Toxicity management and, for sequential treatments, patient and physician awareness, may improve adherence.

Aim To determine the adequacy of chemotherapy received dose intensity (RDI) in breast cancer treatment in a general population and to identify factors that influence RDI. Methods A retrospective analysis of breast cancer patients who commenced a course of i.v. chemotherapy in 2008 was undertaken. Data were collected on patient and tumor characteristics, chemotherapy regimen, dose (including delays, reductions and the reasons for these), granulocyte colony-stimulating factor (G-CSF) use and febrile neutropenia incidence. RDI was calculated using the planned and actual dose received and time taken. A level of ≥85% RDI was considered acceptable for treatment given with curative intent. Results In all, 131 patients (aged 28 to 77 years) received chemotherapy in adjuvant (n = 76, 58%), neoadjuvant (n = 11, 8%) and metastatic settings (n = 44, 34%). RDI did not reach 85% for 12% adjuvant, 36% neoadjuvant and 34% metastatic cases (χ2 = 10.55, P = 0.005). Overall, 43% of patients received G-CSF. Conclusion Acceptable chemotherapy RDI was delivered for most patients in the adjuvant setting but not in the neoadjuvant setting. G-CSF treatment contributed to the optimization of dose intensity in the adjuvant setting only. Dose intensity in the metastatic setting was considered satisfactory where quality of life is the primary focus. Other factors can be modified to improve RDI.

Background The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. Patients and methods Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF) ≥55% were randomized (1 : 2) to doxorubicin 60 mg/m2 (A) + cyclophosphamide 600 mg/m2 (C) every 21 days (q21d) for four cycles or PLD 35 mg/m2 + C q21d + trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m2 with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. Results Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n = 11; 95% confidence interval (CI) 9.7% to 30.9%] with A + C → T + H and 4.2% (n = 5; 95% CI 1.4% to 9.5%) with PLD + C + H → T + H (P = 0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P = 0.0014). Conclusion PLD + C + H → T + H is feasible and results in lower early cardiotoxicity rates compared with A + C → T + H.

The management of HER2-positive metastatic breast cancer, a disease renowned for its aggressive natural history, has been revolutionized by the introduction of trastuzumab. Indeed, outcomes for patients with HER2-positive advanced breast cancer are now equivalent to, if not better than, those of their HER2-negative counterparts. Since the pivotal registration trial, a wealth of new clinical data has emerged regarding the use of trastuzumab in a variety of clinical contexts - adding to the evidence but also highlighting areas of uncertainly and debate. These include the optimal partner chemotherapy(ies) to trastuzumab; the effectiveness of combining trastuzumab with endocrine therapy; the benefits of continuing trastuzumab after progression on a trastuzumab-containing regimen; and the role of trastuzumab in locally advanced and inflammatory breast cancer. In this paper we review major clinical trials addressing these questions, clinical recommendations that can be made as a result, and the strength of evidence that supports them. Finally, we identify areas of ongoing uncertainty, and propose recommendations for future research in this field.

Aromatase inhibitor induced musculoskeletal syndrome is experienced by approximately half of women taking aromatase inhibitors, impairing quality of life and leading some to discontinue treatment. Evidence for effective treatments is lacking. We aimed to understand the manifestations and impact of this syndrome in the Australian breast cancer community, and strategies used for its management. A survey invitation was sent to 2390 members of the Breast Cancer Network Australia Review and Survey Group in April 2014. The online questionnaire included 45 questions covering demographics, aromatase inhibitor use, clinical manifestations and risk factors for the aromatase inhibitor musculoskeletal syndrome, reasons for treatment discontinuation and efficacy of interventions used. Aromatase inhibitor induced musculoskeletal syndrome was reported by 302 (82 %) of 370 respondents. Twenty-seven percent had discontinued treatment for any reason and of these, 68 % discontinued because of the musculoskeletal syndrome. Eighty-one percent had used at least one intervention from the following three categories to manage the syndrome: doctor prescribed medications, over-the-counter/complementary medicines or alternative/non-drug therapies. Anti-inflammatories, paracetamol (acetaminophen) and yoga were most successful in relieving symptoms in each of the respective categories. Almost a third of respondents reported that one or more interventions helped prevent aromatase inhibitor discontinuation. However, approximately 20 % of respondents found no intervention effective in any category. We conclude that aromatase inhibitor induced musculoskeletal syndrome is a significant issue for Australian women and is an important reason for treatment discontinuation. Women use a variety of interventions to manage this syndrome; however, their efficacy appears limited.

Aims: The aims of this analysis were to examine levels of unmet needs and depression among carers of people newly diagnosed with cancer and to identify groups who may be at higher risk, by examining relationships with demographic characteristics. Methods: One hundred and fifty dyads of people newly diagnosed with cancer and their carers, aged 18 years and older, were recruited from four Australian hospitals. People with cancer receiving adjuvant cancer treatment with curative intent, were eligible to participate. Carers completed the Supportive Care Needs Survey-Partners & Caregivers (SCNS-P& C45), and both carers and patients completed the Centre of Epidemiologic-Depression Scale (CES-D). Results: Overall, 57% of carers reported at least one, 37% at least three, 31% at least five, and 15% at least 10 unmet needs; the most commonly endorsed unmet needs were in the domains of information and health care service needs. Thirty percent of carers and 36% of patients were at risk of clinical depression. A weak to moderate positive relationship was observed between unmet needs and carer depression (r = 0.30, p < 0.001). Carer levels of unmet needs were significantly associated with carer age, hospital type, treatment type, cancer type, living situation, relationship status (in both uni- and multi-factor analysis); person with cancer age and carer level of education (in unifactor analysis only); but not with carer gender or patient gender (in both uni- and multi-factor analyses). Conclusion: Findings highlight the importance of developing tailored programmes to systematically assist carers who are supporting patients through the early stages of cancer treatment. Refereed/Peer-reviewed

Improvements in the treatment of metastatic HER2-positive breast cancer constitute one of the great advances in breast cancer medicine of the last generation. From being a highly aggressive fatal condition, the use of anti-HER2-targeted therapies, in particular trastuzumab, has led to significant improvements in disease outcomes. There are reports of increasing numbers of patients alive and well more than 5 years from diagnosis of metastatic disease. Nevertheless, there remain many complex and clinically difficult scenarios where there is little in the way of randomized evidence or published guidelines to guide decision making. As a companion piece to our review of HER2-targeted therapies in the metastatic setting, we decided to focus on a series of clinical scenarios that fell outside of the standard trial-based settings and where opinions and guidance from experienced clinicians and experts in the field would be considered useful to help develop safe and effective treatment strategies. The following eight cases were put forward by our panel of experts, voted on by their peers to select the most relevant and interesting cases, and the discussions worked on by teams of two followed by review and commentary by another team of two.

We aimed to systematically review and summarize data from the available clinical trials that examined the treatment of HER2-positive metastatic breast cancer.We reviewed phase 2 and 3 studies in which an anti-HER2 agent was used in one or both arms of the study. While formal meta-analysis was not possible for such a heterogeneous group of trials, resulting forest plots outline some generalizable findings.There is strong evidence that the addition of an anti-HER2 agent to standard chemo- or endocrine therapy improves clinically relevant measurable outcomes. There is also consistent evidence that initial treatment with trastuzumab alone (and subsequent use of a cytotoxic) is inferior to the initial combination of trastuzumab plus chemotherapy, and that either T-DM1 or dual anti-HER2 agents are superior to single anti-HER2 agent regimens. There is no strong evidence that the use of more than one cytotoxic agent together with an anti-HER2 agent confers any benefit over a single cytotoxic, anti-HER2 combination.This review provides a strong evidence base for current clinical practice with a discussion of treatment in the Australian setting.

Carers provide extended and often unrecognized support to people with cancer. The aim of this study is to test the hypothesis that excessive carer burden is modifiable through a telephone outcall intervention that includes supportive care, information and referral to appropriate psycho-social services. Secondary aims include estimation of changes in psychological health and quality of life. The study will determine whether the intervention reduces unmet needs among patient dyads. A formal economic program will also be conducted. This study is a single-blind, multi-centre, randomized controlled trial to determine the efficacy and cost-efficacy of a telephone outcall program among carers of newly diagnosed cancer patients. A total of 230 carer/patient dyads will be recruited into the study; following written consent, carers will be randomly allocated to either the outcall intervention program (n = 115) or to a minimal outcall / attention control service (n = 115). Carer assessments will occur at baseline, at one and six months post-intervention. The primary outcome is change in carer burden; the secondary outcomes are change in carer depression, quality of life, health literacy and unmet needs. The trial patients will be assessed at baseline and one month post-intervention to determine depression levels and unmet needs. The economic analysis will include perspectives of both the health care sector and broader society and comprise a cost-consequences analysis where all outcomes will be compared to costs. This study will contribute to our understanding on the potential impact of a telephone outcall program on carer burden and provide new evidence on an approach for improving the wellbeing of carers. Australian New Zealand Clinical Trials Registry ACTRN: 12613000731796 .

The profound estrogen depletion caused by aromatase inhibitors (AIs) is associated with musculoskeletal symptoms, but the underlying pathophysiology remains unclear.To assess the effects of AI therapy on structural changes in knee cartilage and subchondral bone over 2 years in postmenopausal women. Setting and participants Thirty women with breast cancer, mean age 58.5 (standard deviation ± 5.6) years and 62 healthy controls, mean age 56.5 (standard deviation ± 4.6) years.Annualized changes in tibial cartilage volume and subchondral bone area, and worsening of tibiofemoral cartilage defects from paired knee magnetic resonance imaging 2 years apart were compared between the two groups.The AI-treated women had significantly greater expansion of the tibial plateau than the control group. The mean annualized differences, after adjusting for age, body mass index and baseline bone area, were 22.1 mm(2) (95% confidence interval (CI) 7.6-36.6, p = 0.003) for the medial tibial plateau and 19.1 mm(2) (95% CI 9.6-28.5, p0.001) for the lateral tibial plateau. The annual change in tibial cartilage volume and the worsening of cartilage defects did not differ between women taking AI therapy and controls.AI therapy is associated with knee subchondral bone expansion knee with no effect on knee cartilage in postmenopausal women without pre-existing joint symptoms. This suggests the effect of severe estrogen depletion on knee is on bone, with the tibial bone expansion most likely a response to mechanical load in the setting of bone loss. Whether this then results in an increased risk of knee osteoarthritis will need to be determined.

Purpose Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged overall survival (OS) compared with tamoxifen monotherapy. Patients and Methods Of 8,010 postmenopausal women with hormone receptor–positive, early breast cancer enrolled on the Breast International Group (BIG) 1-98 study, 4,922 were randomly assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen. Of 2,459 patients enrolled in the tamoxifen treatment arm, 619 (25.2%) selectively crossed over to either adjuvant or extended letrozole after initial trial results were presented in January 2005. To gain better estimates of relative treatment effects in the presence of selective crossover, we used inverse probability of censoring weighted (IPCW) modeling. Results Weighted Cox models, by using IPCW, estimated a statistically significant, 18% reduction in the hazard of an OS event with letrozole treatment (hazard ratio [HR], 0.82; 95% CI, 0.70 to 0.95). Estimates of 5-year OS on the basis of IPCW were 91.8% and 90.4% for letrozole and tamoxifen, respectively. The HRs of DFS and TDR events by using IPCW modeling were 0.83 (95% CI, 0.74 to 0.94) and 0.80 (95% CI, 0.67 to 0.94), respectively (P < .05 for DFS, OS, and TDR). Median follow-up was 74 months. Conclusion Adjuvant treatment with letrozole, compared with tamoxifen, significantly reduces the risk of death, the risk of recurrent disease, and the risk of recurrence at distant sites in postmenopausal women with hormone receptor–positive breast cancer.

Background Monotherapy with nanoparticle albumin-bound ( nab )-paclitaxel has demonstrated improved efficacy and safety compared with solvent-based paclitaxel and docetaxel. Design A comprehensive review of all reported studies of nab -paclitaxel combinations with other agents in all breast cancer settings was undertaken. Results Most studies reviewed are small, phase II and non-comparative. Combinations studied included nab -paclitaxel plus trastuzumab and/or bevacizumab (with or without additional cytotoxic agents), gemcitabine, capecitabine, carboplatin, or lapatinib. The majority of metastatic and neoadjuvant studies demonstrated satisfactory efficacy and safety for nab -paclitaxel combinations, although conclusions regarding comparison with solvent-based taxane (SBT) regimens are not possible. The two adjuvant studies confirmed the safety of nab -paclitaxel combinations in this setting. Conclusions Although results of this review indicate that nab -paclitaxel may be an appropriate substitute for SBTs in combination regimens, additional research is required to confirm the place and cost effectiveness of these combinations before nab -paclitaxel could be recommended routinely in all settings.

Purpose To explore potential differences in efficacy, treatment completion, and adverse events (AEs) in elderly women receiving adjuvant tamoxifen or letrozole for five years in the Breast International Group (BIG) 1-98 trial. Methods This report includes the 4,922 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial. The median follow-up was 40.4 months. Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was used to examine the patterns of differences in disease-free survival and incidences of AEs according to age. In addition, three categoric age groups were defined: “younger postmenopausal” patients were younger than 65 years (n = 3,127), “older” patients were 65 to 74 years old (n = 1,500), and “elderly” patients were 75 years of age or older (n = 295). Results Efficacy results for subpopulations defined by age were similar to the overall trial results: Letrozole significantly improved disease-free survival (DFS), the primary end point, compared with tamoxifen. Elderly patients were less likely to complete trial treatment, but at rates that were similar in the two treatment groups. The incidence of bone fractures, observed more often in the letrozole group, did not differ by age. In elderly patients, letrozole had a significantly higher incidence of any grade 3 to 5 protocol-specified non-fracture AE compared with tamoxifen (P = .002), but differences were not significant for thromboembolic or cardiac AEs. Conclusion Adjuvant treatment with letrozole had superior efficacy (DFS) compared with tamoxifen in all age groups. On the basis of a small number of patients older than 75 years (6%), age per se should not unduly affect the choice of adjuvant endocrine therapy.

Purpose Previous analyses of the Breast International Group (BIG) 1-98 four-arm study compared initial therapy with letrozole or tamoxifen including patients randomly assigned to sequential treatment whose information was censored at the time of therapy change. Because this presentation may unduly reflect early events, the present analysis is limited to patients randomly assigned to the continuous therapy arms and includes protocol-defined updated results. Patients and Methods Four thousand nine hundred twenty-two of the 8,028 postmenopausal women with receptor-positive early breast cancer randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. Disease-free survival (DFS) was the primary end point. Results At a median follow-up time of 51 months, we observed 352 DFS events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports. Patients on tamoxifen experienced more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure. Conclusion The present updated analysis, which was limited to patients on monotherapy arms in BIG 1-98, yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.

Abstract #1148 Background: Women aged under 55 receiving breast cancer treatment frequently experience temporary or permanent menopause as a result. Although defining menopause status in these patients is problematic it fundamentally influences subsequent medical management. No definitive data or consensus exists to guide what surveillance is required in these women, particularly with respect to treatment with aromatase inhibitors (AIs) and/or ovarian suppression and for contraceptive advice.The ENHANCE Group, first convened in Australia in 2006, consists of 19 members, comprising Medical Oncologists, Breast Surgeons, Endocrinologists, Gynaecologists and a Consumer Representative. The aim of the Group is to develop practical advice on the management of QoL and adverse event issues associated with hormonal therapy of breast cancer in areas where high-level evidence is insufficient to inform practice. The Group produces recommendations for healthcare professionals and information leaflets for patients. All recommendations are supported with the maximum evidence available together with broad expert opinion. Methods:A review of the literature identified information regarding the definition of menopause, tests of menopause status and likelihood of menopause following different adjuvant chemotherapy regimens. Data on the likelihood of return of ovarian function was also identified. In addition, the use and benefit of ovarian function suppression and AIs for treatment of different subpopulations of breast cancer patients was reviewed. Using this review and expert opinion provided by members of the Group, an algorithm for determination of menopausal category was developed. Management recommendations, according to menopausal category were then determined. Results:Five distinct menopause categories were identified: Premenopausal, Postmenopausal, Very Low, Low, and Moderate potential for ovarian function recovery. Menopausal status prior to adjuvant chemotherapy, type of adjuvant treatment, age, duration of amenorrhoea, oestradiol and FSH levels and use of tamoxifen determined placement into the categories. The algorithm includes suggested monitoring practice, both clinical and biochemical, for each of the menopause categories and guidance for patients who have had a hysterectomy. The recommendations indicate: (i)contraceptive advice according to age and menopause category; (ii)appropriate use of AIs with suggested monitoring practices; (iii)monitoring suggestions for patients where ovarian function suppression may be appropriate (iv)advice to be provided to patients to assist in monitoring menopausal status. A separate information sheet was developed to inform patients about menopause monitoring. Conclusions:Ovarian function can return after a considerable period of amenorrhoea in patients undergoing systemic treatment for breast cancer. Return of ovarian function influences endocrine treatment of breast cancer, but it is often difficult to monitor accurately, and an appropriate schedule has not been investigated. Our work provides evidence-based recommendations (including expert opinion) for best practice in this area. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1148.