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Background Prospective data on the risk of recurrence among women with hormone receptor-positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking. Methods We conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial. Results Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort. Conclusions Among select women with previous hormone receptor-positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.).

Background NSABP B-42 evaluated extended letrozole therapy (ELT) in postmenopausal breast cancer patients who were disease-free after 5 years of aromatase inhibitor-based (AI) therapy. Seven-year results demonstrated a non-statistically significant trend in disease-free survival (DFS) in favor of ELT. We present 10-year outcome results. Methods In this double-blind, phase 3 trial, patients with stage I-IIIA hormone receptor-positive breast cancer, disease-free after 5 years of an AI or tamoxifen followed by an AI, were randomized to 5 years of letrozole or placebo. Primary endpoint was DFS, defined as time from randomization to breast cancer recurrence, second primary malignancy, or death. All statistical tests are two-sided. Results Between 09/06 and 01/10, 3,966 patients were randomized (letrozole: 1,983; placebo: 1,983). Median follow-up time for 3,923 patients included in efficacy analyses was 10.3 years. There was statistically significant improvement in DFS in favor of letrozole compared to placebo (Hazard Ratio [HR]=0.85; 95%CI 0.74-0.96, p-value = 0.01, 10-year DFS: placebo = 72.6%, letrozole = 75.9%, absolute difference 3.3%). There was no difference in the effect of letrozole on overall survival (OS) (HR = 0.97, 95%CI 0.82-1.15, p-value = 0.74). Letrozole significantly reduced breast cancer-free interval (BCFI) events (HR = 0.75, 95%CI 0.62-0.91, p-value = 0.003, absolute difference in cumulative incidence: 2.7%) and distant recurrences (DR) (HR = 0.72, 95%CI 0.55-0.92, p-value = 0.01, absolute difference: 1.8%). The rates of osteoporotic fractures and arterial thrombotic events did not differ between treatment groups. Conclusions The beneficial effect of ELT on DFS persisted at 10 years. Letrozole also significantly improved BCFI and DR without improving OS. Careful assessment of potential risks and benefits is necessary for selecting appropriate candidates for ELT. Clinical Trials registration NCT00382070

Background: De novo and acquired resistance to HER2 directed therapy is frequently encountered. Upregulation of the phosphatidylinositol-3-kinase (PI3K) pathway is an important mediator of treatment resistance. This can occur through an activating mutation of the PIK3CA gene or PTEN loss. PIK3CA mutations are present in approximately 20% of HER2 positive breast cancers and as such, the PI3K pathway has emerged as an attractive target for restoring sensitivity to HER2 directed therapy. Methods: We performed a single arm, multicentre, open label Phase Ib/II trial. Patients (pts) with advanced HER2-positive breast cancer whose disease had progressed on at least 1 line of Trastuzumab/T-DM1 based treatment in the metastatic setting were eligible if they met following criteria: ECOG PS ≤ 2 and adequate organ function. Pts with treated, controlled brain metastases were permitted to enrol. Exclusion criteria included uncontrolled hypertension or diabetes mellitus. Pts on Phase IB were treated according to a 6+6 study design with a dose escalation schedule of Copanlisib IV (level 1 = 45mg, level 2 = 60mg) on Day 1, 8 and 15 of a 28-day cycle along with a fixed dose of Trastuzumab 2mg/kg weekly. Phase II treatment was the MTD (maximum tolerated dose) of Copanlisib in combination with Trastuzumab. Archival tumour tissue, voluntary biopsies and serial plasma samples were collected for genomic sequencing. Primary endpoints were MTD (Phase I) and clinical benefit rate (CBR) which was defined as complete response (CR) or partial response (PR) at any time point; or stable disease (SD) lasting at least 24 weeks (Phase II). Secondary endpoints included safety and tolerability, tumor response rate, duration of response, time to treatment failure (TTF) and progression free (PFS) and overall survival (OS). Results: Twelve pts were enrolled in Phase IB. No dose limiting toxicity was observed. The MTD was established as Copanlisib 60mg and Trastuzumab 2mg/kg. Fourteen pts were enrolled in Phase II (6 pts treated at the MTD in Phase IB were included in the final Phase II analysis resulting in a total of 20 pts). The median number of lines of prior treatment in the metastatic setting was 3 (1-8). The most common grade 3-4 toxicities encountered in the Phase Ib/II cohorts included hypertension (n=7, 27%), hyperglycaemia (n=2, 8%) and vomiting (n=2, 8%). Three pts discontinued treatment due to toxicity. The median follow-up for the Phase II cohort was 7.5 months (95% CI 6.0-14.5). PR was observed in 4 pts (20%) and SD (at any time point) was seen in 8 pts (40%). The CBR was 30% (n=6). The duration of response was 15.0 weeks (95% CI 4.9 - 16.1). The median TTF was 11.9 weeks (95% CI 7.5 - 21.1). The median PFS was 3.0 mo (95% CI 0.2 - 5.8) and OS was 14.0 mo (95% CI 5.2-22.8). At the time of analysis, 9 of 20 patients were alive. PIK3CA mutations were detectable in the archival tissue of 11 of 26 pts (42%). PIK3CA hotspot mutations (H1047R, E542K and E545K) were detectable in the plasma of all 26 pts at various points throughout treatment. Pre and post treatment biopsies of 2 pts in the Phase IB trial revealed somatic mutations in DNAH3 and TRRAP, the latter of which encodes a PI3K-like protein kinase. Targeted next generation sequencing was performed on the circulating tumour DNA of 20 pts in the Phase II cohort taken before, during and after treatment to further validate these findings and to assess for other mechanisms of response or resistance. The final translational results will be presented at the meeting. Conclusions: The combination of Copanlisib and Trastuzumab is a safe and tolerable regimen and is associated with clinical efficacy in a heavily pre-treated metastatic HER2-positive breast cancer population. Translational studies may have identified novel resistance biomarkers in this pt cohort. Citation Format: Lisa Prior, Niamh M Keegan, Simon J Furney, Janice M Walshe, Giuseppe Gullo, John Crown, M John Kennedy, Diarmuid Smith, John McCaffrey, Catherine M Kelly, Keith Egan, Jennifer Kerr, Mark Given, Niall Sheehy, Peter O'Donovan, Andres Hernando, Ausra Teiserskiene, Imelda Parker, Elaine Kay, Ray McDermott, Maccon M Keane, Seamus O'Reilly, Liam Grogan, Oscar Breathnach, Patrick G Morris, Sinead Toomey, Bryan T Hennessy. Phase Ib/II trial evaluating safety and efficacy of copanlisib (PI3K inhibitor) and trastuzumab in pre-treated advanced HER2-positive breast cancer: Results from the PantHER study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-08.

Background Menopause may cause a constellation of symptoms that affect quality of life. Many women will have menopause induced or exacerbated by treatment for cancer whether that be through surgery, chemotherapy, radiotherapy, or anti-endocrine therapy. As treatments advance, the number of people living with and beyond a cancer diagnosis is set to increase over the coming years meaning more people will be dealing with the after effects of cancer and its treatment. Aims This review aims to summarise available data to guide clinicians treating women with menopausal symptoms after the common cancer diagnoses encountered in Ireland. The use of menopausal hormone therapy is discussed as well as non-hormonal and non-pharmacological options. Conclusions Managing menopausal symptoms is an important consideration for all physicians involved in the care of people living with and beyond a cancer diagnosis. High-quality data may not be available to guide treatment decisions, and, thus, it is essential to take into account the impact of the symptoms on quality of life as well as the likelihood of recurrence in each individual case.

Objective In the PALOMA-2 trial, palbociclib in combination with letrozole prolonged progression-free survival (PFS) and exhibited an acceptable safety profile in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). This post hoc analysis of PALOMA-2 evaluated the efficacy and safety of palbociclib plus letrozole in patients with preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). Methods Postmenopausal patients without prior treatment for ABC were randomized 2:1 to receive palbociclib (125 mg/d on a 3 weeks on/1 week off schedule) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. Patients were grouped by the following MedDRA SOC preexisting conditions: gastrointestinal, musculoskeletal, metabolic, and vascular/cardiac. Median PFS was estimated by the Kaplan-Meier method, and treatment emergent adverse events (AEs) were compared between treatment arms within each preexisting condition subgroup. Results At baseline, 276 (41.4 %) patients had preexisting gastrointestinal disorders, 390 (58.6 %) had musculoskeletal disorders, 259 (38.9 %) had metabolic disorders, and 382 (57.4 %) had vascular/cardiac disorders. Baseline characteristics were similar between subgroups and between each arm within subgroups. Regardless of baseline preexisting condition, palbociclib plus letrozole prolonged PFS compared with placebo plus letrozole. Treatment-emergent AEs associated with palbociclib plus letrozole and dose modifications due to AEs were similar across preexisting condition subgroups. Conclusion This post hoc analysis of PALOMA-2 demonstrated a favorable effect of palbociclib on PFS and a safety profile consistent with previous observations, regardless of underlying preexisting condition. Pfizer Inc (NCT01740427)., Highlights • Preexisting conditions can affect the safety and efficacy of breast cancer therapies. • This is a post hoc analysis of patients with preexisting conditions from PALOMA-2. • Palbociclib prolonged median PFS, regardless of preexisting condition. • Within each treatment arm, AEs were similar regardless of preexisting condition.

Background Pre-treatment tumour-associated lymphocytes (TILs) and stromal lymphocytes (SLs) are independent predictive markers of future pathological complete response (pCR) in HER2-positive breast cancer. Whilst studies have correlated baseline lymphocyte levels with subsequent pCR, few have studied the impact of neoadjuvant therapy on the immune environment. Methods We performed TIL analysis and T-cell analysis by IHC on the pretreatment and ‘On-treatment’ samples from patients recruited on the Phase-II TCHL (NCT01485926) clinical trial. Data were analysed using the Wilcoxon signed-rank test and the Spearman rank correlation. Results In our sample cohort (n = 66), patients who achieved a pCR at surgery, post-chemotherapy, had significantly higher counts of TILs (p = 0.05) but not SLs (p = 0.08) in their pre-treatment tumour samples. Patients who achieved a subsequent pCR after completing neo-adjuvant chemotherapy had significantly higher SLs (p = 9.09 × 10–3) but not TILs (p = 0.1) in their ‘On-treatment’ tumour biopsies. In a small cohort of samples (n = 16), infiltrating lymphocyte counts increased after 1 cycle of neo-adjuvant chemotherapy only in those tumours of patients who did not achieve a subsequent pCR. Finally, reduced CD3 + (p = 0.04, rho = 0.60) and CD4 + (p = 0.01, rho = 0.72) T-cell counts in 'On-treatment' biopsies were associated with decreased residual tumour content post-1 cycle of treatment; the latter being significantly associated with increased likelihood of subsequent pCR (p Conclusions The immune system may be ‘primed’ prior to neoadjuvant treatment in those patients who subsequently achieve a pCR. In those patients who achieve a pCR, their immune response may return to baseline after only 1 cycle of treatment. However, in those who did not achieve a pCR, neo-adjuvant treatment may stimulate lymphocyte influx into the tumour.

Background: The use of the 21-gene recurrence score assay (RS) has reduced chemotherapy (CT) administration in patients with hormone receptor (HR)-positive, HER-2 negative, lymph-node negative, early stage breast cancer (ESBC). Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancers. This study uses real world data to assess (1) the effect of RS testing on treatment decision making in patients with ILC and (2) the economic benefit of testing in this subgroup. Methods: From October 2011 to February 2019, a retrospective, cross-sectional, observational study was conducted on HR+, HER-2 negative, lymph-node negative, ESBC patients with ILC who had RS testing in Ireland. For the decision impact analysis, a survey of Irish breast medical oncologists presumed that, without RS testing, CT would be recommended to patients with histological grade (G) 2 and 3 tumours and not for G1 tumours. In accordance with TAILOR-x results, patients were classified overall as low risk (RS≤25) and high risk (RS>25) and patients ≤50 years old were low risk (RS 0-15), intermediate risk (RS 16-25), and high risk (RS>25). Data were collected from electronic patient records. Descriptive statistics were used. Cost data were obtained from the National Healthcare Pricing Regulatory Authority. The economic analysis was adjusted for changing treatment and assay costs over the study period. Results: 166 patients with ILC were identified. Mean age was 59 years. Mean tumour size was 2.3cm (range 0.7-5.8). The majority had G2 tumors (n=152, 92%) with a small number of G3 (n=7, 4%) and G1 (n=7,4%). Overall, 153 patients (92.2%) had a low RS (≤25), 12 (7.2%) had high RS (>25), and 1(0.6%) was unknown. All 12 patients with RS>25 had G2 tumours, 6/12 (50%) had tumour size >3cm, 4(33.3%) were PR+ and 8(66.7%) were PR negative. In 29/166 (17.5%) patients, aged ≤50 at diagnosis, RS was ≤15 in 16(55%), 16-20 in 6(21%), 21-25 in 5(17%), >25 in 1(3.5%) and unknown in 1(3.5%). The majority of these patients (27, 93%) had G2 tumours, 1 had G1 and 1 had G3. Post RS testing 124 patients (74.5%) had a change in CT recommendation; all from CT to hormone therapy. In total, only 35 patients (21%) received CT. In this group, RS was 0-15 in 3(9%), RS 16-25 in 19(54%), RS >25 in 12 (34%) and unknown in 1(3%). Eight of 35 patients (23%) were aged ≤50. The most common CT regimen administered was docetaxel plus cyclophosphamide (TC). RS testing achieved a 78% reduction in chemotherapy use. This resulted in savings of €900,000 in treatment costs. With the incorporation of the assay cost, the net savings totalled approximately €400,000. Conclusions: Ireland was the first public health care system to reimburse the 21-gene recurrence score assay in Europe. There is limited evidence demonstrating the benefits of RS in ILC. In our study, the use of the test has resulted in a 78% reduction in chemotherapy use in an Irish ILC patient population and a substantial cost saving (greater than €400,000) to the Irish Healthcare System. Citation Format: Mehala Tharmabala, Lynda McSorley, Fathiya Al Rahbi, Evoy Denis, James G Geraghty, Rothwell Jane, Damian McCartan, Enda McDermott, Maccon M Keane, John Kennedy, Seamus O'Reilly, Steve Millen, John Crown, Lilian Mary Smyth, Catherine Margaret Kelly, Prichard Ruth, Cecily Quinn, Janice M Walshe. An analysis of the clinical and economic impact of the 21-gene recurrence score (RS) in invasive lobular early-stage breast cancer (ESBC) in Ireland [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 PS4-23.

Background: Pregnancy is a major concern for young breast cancer (BC) survivors. Conception after BC in women with hormone receptor positive (HR+) disease is affected by the standard 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may be waning. The POSITIVE Trial (IBCSG 48-14/BIG 8-13/Alliance A221405/NCT02308085) investigates the impact of temporary ET interruption to allow pregnancy. Methods: POSITIVE enrolled premenopausal women with stage I-III HR+ early BC, ≤42 years of age, who had received adjuvant ET (SERM alone, ovarian function suppression (OFS) plus SERM or AI) for 18 to 30 months, and wished to interrupt ET to attempt pregnancy. An interruption of ET for up to 2 years was foreseen to allow pregnancy (after a 3-month ET washout period), delivery, and breastfeeding if desired/feasible. Resumption of ET to complete 5-10 years of treatment was planned as soon as pregnancy/breastfeeding was completed or after it was ensured conception was not possible. We report baseline characteristics of participants enrolled in POSITIVE by region of enrollment. Results: From 12/2014 to 12/2019, 518 participants were enrolled at 116 centers in 20 countries across 4 continents. The table shows the baseline characteristics of the enrolled women. Several differences were seen across regions: A higher proportion of participants Conclusion: Regional variation of baseline characteristics of women enrolled in the POSITIVE trial may provide important insights into different medical and sociocultural attributes and attitudes of the study participants and investigators from those regions. Affiliation: POSITIVE Investigators, International Breast Cancer Study Group, Alliance for Clinical Trials in Oncology, Breast International Group, North American Breast Cancer Group CharacteristicRegion: Europe / North America / Asia-Pacific61% / 23% / 16%Median age at enrollment, yrs (IQR)37 (33-39)Caucasian race77%No children prior to enrollment74%Prior fertility preservation measures taken51%Stage I / II46% / 45%0 / 1 positive nodes65% / 21%Grade 2 / 348% / 33%HER2-negative74%Mastectomy46%Chemotherapy61%ET: SERM alone / SERM+OFS / AI+OFS41% / 35% / 16%Median duration of prior ET, mos (IQR)23 (20-27) Citation Format: Ann H Partridge, Samuel M Niman, Monica Ruggeri, Fedro A Peccatori, Hatem A Azim, Jr, Marco Colleoni, Cristina Saura, Chikako Shimizu, Anna Barbro Sætersdal, Judith Kroep, Ellen Warner, Virginia F Borges, Andrea Gombos, Akemi Kataoka, Christine Rousset-Jablonski, Simona Borstnar, Hideko Yamauchi, Jeong Eon Lee, Janice M Walshe, Manuel Ruíz Borrego, Halle CF Moore, Christobel Saunders, Fatima Cardoso, Snezana Susnjar, Vesna Bjelic-Radisic, Karen L Smith, Martine Piccart, Larissa A Korde, Aron Goldhirsch, Richard D Gelber, Olivia Pagani. Baseline characteristics of women enrolled in the POSITIVE trial (pregnancy outcome and safety of interrupting therapy for women with endocrine responsIVE 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 PS12-17.

Background: In the PALOMA-2 trial, PAL + letrozole (LET) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + LET in pts with ER+/HER2– ABC. This post hoc analysis assessed efficacy and safety of PAL + LET in pts from PALOMA-2 with baseline preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). Methods: Postmenopausal pts with ER+/HER2– ABC received PAL (125 mg/d, 3/1 schedule) + LET (2.5 mg/d, continuous) or PBO + LET. Pts were grouped by the following MedDRA SOC preexisting conditions: Gastrointestinal, Musculoskeletal, Metabolism, and Vascular/Cardiac. Baseline characteristics, PFS, and safety were assessed. Results: At baseline, 41.4% of pts had preexisting gastrointestinal disorders, 58.6% musculoskeletal disorders, 38.9% metabolism disorders, and 57.4% vascular/cardiac disorders. Baseline characteristics were similar between treatment arms within each subgroup and also between subgroups. Within each subgroup, ≥40% of pts also had ≥1 of the other coexisting conditions. Median PFS (mPFS) was significantly longer with PAL + LET vs PBO + LET regardless of preexisting condition (Table). In general, adverse events (AEs) were more frequent with PAL + LET in all subgroups; neutropenia was most common. Within each treatment arm, AEs and dose modifications due to AEs were similar regardless of preexisting condition. Conclusion: PAL + LET showed prolonged PFS and a consistent safety profile regardless of baseline preexisting condition in pts with ER+/HER2– ABC. Clinical trial identification: Pfizer Inc (NCT01740427) TablePreexisting ConditionPAL + LETPBO + LETPAL + LET vs PBO + LETnmPFS (95% CI)nmPFS (95% CI)HR (95% CI)P ValueGastrointestinal17627.6 (17.5–33.1)10013.6 (11.0–18.5)0.57 (0.42–0.78) Citation Format: Karen Gelmon, Janice M Walshe, Reshma Mahtani, Anil A Joy, Meghan Karuturi, Patrick Neven, Dongrui Ray Lu, Sindy Kim, Patrick Schnell, Eustratios Bananis, Lee Schwartzberg. Efficacy and safety of palbociclib (PAL) in patients (pts) with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with preexisting conditions: A post hoc analysis of PALOMA-2 [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 PS10-14.

The human epidermal growth factor receptor 2 (HER2), is amplified and/or overexpressed in approximately 15%-20% of breast cancers. Targeting of the HER2 receptor with the humanized monoclonal antibody trastuzumab in combination with chemotherapy has become the backbone of treatment for both early stage and metastatic breast cancer for the last 2 decades. Relapsed or de novo metastatic HER2-positive breast cancer essentially remains an incurable disease. Nonetheless, with advances in therapeutics, survival rates in this group continue to increase with median survival now in excess of 57 months. First line systemic therapy for HER2-positive metastatic breast cancer using taxane chemotherapy combined with trastuzumab and pertuzumab, and second line therapy with trastuzumab emtansine, are well established. Recent studies of small molecule oral tyrosine kinase inhibitors such as tucatinib and neratinib, and antibody drug conjugates such as trastuzumab deruxtecan further improve outcomes. Major treatment challenges remain in the areas of brain metastases and development of drug resistance. This review details an up to date analysis of current and emerging treatments of metastatic HER2-positive breast cancer.

Background In PALOMA-2, palbociclib + letrozole significantly prolonged progression-free survival (PFS) versus placebo + letrozole in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2−) advanced breast cancer (ABC). We investigated clinical outcomes of patients who achieved or did not achieve a confirmed objective response (OR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (data cutoff: May 31, 2017). Patients and Methods Postmenopausal patients untreated for ER+/HER2− ABC were randomized 2:1 to palbociclib + letrozole or placebo + letrozole. Median PFS, median duration of OR, baseline characteristics, and palbociclib exposure were compared in patients with or without OR by treatment arm. Results In the intent-to-treat population, OR was achieved by 194 (44%) of 444 and 77 (35%) of 222 patients in the palbociclib and placebo arms, respectively (odds ratio, 1.5; 95% confidence interval [CI], 1.0-2.1; P = .0156). Regardless of treatment, more OR than non-OR patients had de novo metastatic disease (47%-50% and 28%-31%, respectively) and no prior endocrine therapy (55% and 35%-37%, respectively). Rates of palbociclib dose reduction owing to adverse events were similar regardless of OR (41% and 38%, respectively). Among the patients with OR during the study, approximately 50% achieved OR within the first 3 months regardless of treatment. The median PFS was significantly prolonged with palbociclib + letrozole versus placebo + letrozole in patients with measurable disease in both OR (37.2 months; 95% CI, 28.1 months to not estimable vs. 27.4 months; 95% CI, 22.2-31.1 months; hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .009) and non-OR groups (10.9 months; 95% CI, 8.2-11.2 months vs. 5.6 months; 95% CI, 5.3-8.3 months; hazard ratio, 0.72; 95% CI, 0.54-0.97; P = .016). Conclusions Palbociclib + letrozole provided significant clinical benefit versus placebo + letrozole to patients with ER+/HER2− ABC regardless of achieving RECIST-defined OR. Pfizer; ClinicalTrials.gov : NCT01740427

Background: The 21 gene recurrence score (OncotypeDx ®) is reimbursed in Ireland to guide adjuvant treatment decisions for ER+, LN-negative, human epidermal growth factor receptor 2 (HER2)-negative BC. There is emerging evidence supporting the clinical utility of this test in patients with LN+ disease. Although the exact cut-off for chemotherapy has not been defined in this population, SEER data support the omission of chemotherapy for patients with RS Results: In total, 294 patients were enrolled across the - nine centres. Complete data is available on 123 patients (range 38 to 75, median 54 years), which included two male patients. Of the remaining 121 (98%) patients, 49 (40%) were premenopausal, 26 (21%) perimenopausal and 46 (37%) postmenopausal. The median tumour size was 38 mm (Range 7 to 58 mm). There were 101 (82%) patients with invasive ductal carcinoma, 17 (14%) with lobular carcinoma and 5 (4%) classified as other breast histology. Seventeen patients (14%) had grade 1, 74 (60%) grade 2 and 32 (26%) grade 3 disease. There were 79 (64%) patients with 1 LN+, 35 (29%) with 2 LN+ and 9 (7%) with 3 LN+ status. Overall access to the 21 gene RS test led to a 32% reduction in chemotherapy, 112 (91%) to 72 (59%) patients. This was most notable in patients with ductal histology (91 vs 61) and grade 2 breast cancer (66 vs 41) representing a 24.4% and 20.3% reduction, respectively. Similarly patients with 1 LN+ (71 vs 46) and 2 LN+ (34 vs 21) represented a 20.3% and 9.7% reduction, respectively. This study also identified four patients aged less than 40, for whom chemotherapy was not recommended. The biggest reduction in chemotherapy occurred in women aged over 50 (62 vs 36) at 21.1%. Overall, in 65% of cases, medical oncologists deemed the RS test result significantly changed treatment recommendations. Conclusion: These findings are consistent with results from similar studies in other countries. Broader access to the 21-gene RS could result in a reduction in the use of chemotherapy in Ireland. Citation Format: William J Mullally, Dara Bracken-Clarke, Andrew Padmore, Seamus O'Reilly, Deirdre O’Mahony, Janice Walshe, John Kennedy, Rajnish Gupta, Cathy Kelly, Miriam O'Connor, Karen Duffy, Maccon Keane, Bryan T Hennessy, Patrick G Morris. The impact of the 21 gene recurrence score (RS) on chemotherapy prescribing in estrogen receptor positive (ER+), lymph node positive (LN+) breast cancer (BC) in Ireland: A national, multi-centre, prospective study [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 P3-08-56.

Menopause may cause a constellation of symptoms that affect quality of life. Many women will have menopause induced or exacerbated by treatment for cancer whether that be through surgery, chemotherapy, radiotherapy, or anti-endocrine therapy. As treatments advance, the number of people living with and beyond a cancer diagnosis is set to increase over the coming years meaning more people will be dealing with the after effects of cancer and its treatment.This review aims to summarise available data to guide clinicians treating women with menopausal symptoms after the common cancer diagnoses encountered in Ireland. The use of menopausal hormone therapy is discussed as well as non-hormonal and non-pharmacological options.Managing menopausal symptoms is an important consideration for all physicians involved in the care of people living with and beyond a cancer diagnosis. High-quality data may not be available to guide treatment decisions, and, thus, it is essential to take into account the impact of the symptoms on quality of life as well as the likelihood of recurrence in each individual case.

Aims: This study will aim to assess if a composite intervention which involves a specific evidence-based intervention for management of insomnia and non-hormonal pharmacotherapy to manage vasomotor symptoms (VMS) of menopause can improve quality of life for patients experiencing troublesome VMS after cancer who are not eligible for standard systemic menopausal hormone therapy (MHT). Participants will be asked to nominate a partner or companion to support them during this process as an additional form of support. Background: The menopause transition and its symptoms represent a significant challenge for many patients after cancer treatment, particularly those for whom conventional MHT is contraindicated. These symptoms include hot flushes, night sweats, urogenital symptoms as well as mood and sleep disturbance. These symptoms can exacerbate the consequences of cancer and its treatment. Methods: We will recruit 205 women who meet inclusion criteria and enrol them on a composite intervention which consists of four parts: (1) use of non-hormonal pharmacotherapy for the management of troublesome vasomotor symptoms of menopause tailored to the timing of predominant symptoms, (2) digital cognitive behavioural therapy for insomnia through the web based Sleepio service, (3) access to information regarding self-management strategies for the common symptoms of menopause and their consequences and (4) identification of a partner or other support person who commits to providing support during the study period. Outcomes: The primary outcome will be cancer specific quality of life measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30). Secondary outcomes will include sleep quality, bother/interference of vasomotor symptoms and communication between couples about their cancer diagnosis and their menopause experience. Sleep will be measured using the Sleep Condition Indicator (SCI) tool, bother/interference of vasomotor symptoms will be measured by the Hot Flush Rating Scale (HFRS) and communication will be measured using the Couples’ Illness Communication Scale (CICS). These validated scales will be administered at baseline, four weeks, three months and six months. Registration: This study is registered on ClinicalTrials.gov with number NCT 04766229.

Background: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5–10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy. Methods: POSITIVE enrolled women with stage I-III HR + early breast cancer, ≤42 years, who had received 18–30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration. Findings: From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were, SCOPUS: ar.j, info:eu-repo/semantics/published

Background:The phosphoinositide 3 kinase (PI3K) pathway is important in the oncogenic function of HER2. Aberrant activation of PI3K is implicated in resistance to trastuzumab and other HER2-targeted therapies and is frequent, with up to 22% of HER2 positive breast cancer having a PIK3CA mutation. Copanlisib is a pan-class 1 PI3K inhibitor administered i.v. with low nanomolar activity against both PI3Kα and PI3Kβ. Copanlisib has been shown to re-sensitise trastuzumab resistant cell lines to trastuzumab with synergism seen in some cell lines between copanlisib and HER2 targeted therapy. Trial design: This is a phase Ib open label, single arm adaptive, multi-centre trial of copanlisib in combination with T-DM1. Eligible patients will receive T-DM1 at 3.6mg/kg i.v. on day 1 of a 21-day cycle plus copanlisib. Copanlisib will be administered i.v. according to the dose escalation scheme (dose level 1 is 45mg on days 1 and 8, dose level 2 is 60mg on days 1 and 8, dose level 3 is 60mg on days 1, 8, and 15). Dose level -1 will be 45 mg on day 1 in case dose de-escalation is needed. We will enrol 3 to 6 patients per dose level. All patients in each level must have completed at least the first cycle of therapy before enrolment in the next dose level. Patients not completing the first cycle for a reason other than toxicity will be replaced. Dose escalation and determination of the Maximum Tolerated Dose (MTD) will be based on the occurrence of Dose Limiting Toxicities (DLT). Eligibility criteria:Eligible patients are those with unresectable locally advanced or metastatic HER2-positive BC who previously received trastuzumab and a taxane, separately or in combination. Participants must have adequate organ function and ECOG PS ≤ 2 Objectives:The primary objective is to determine the MTD for copanlisib in combination with T-DM1 in patients with pre-treated unresectable locally advanced or metastatic HER2-positive BC. Secondary objectives include evaluating the safety, efficacy and cardiotoxicity in patients treated with this regimen. Exploratory objectives include examining for predictive biomarkers in tumour tissue and blood or plasma and to examine molecular tumour adaptation to clinical trial therapy. Statistical methods: Patients will be accrued in cohorts of 3 patients according to a standard 3+3 algorithm, with dose escalation and determination of MTD based on the occurrence of DLT, using the usual threshold probability of 33%. The final dose level will be expanded to include a total of 6 additional patients (expansion cohort). Present accrual and target accrual:The trial will start accrual in October 2018. Maximum of 24 patients will be enrolled. Citation Format: Hassan A, Gullo G, O'Reilly S, Ruiz-Borrego M, Toomey S, Grogan L, Breathnach O, Morris PG, Walshe JM, Crown J, O'Mahony D, Falcon A, Egan K, Hernando A, Teiserskiene A, Kelly CM, Coate L, Hennessy BT. Phase Ib clinical trial of coPANlisib in combination with Trastuzumab emtansine (T-DM1) in pre-treated unresectable locally advanced or metastatic HER2-positive breAst cancer (BC) “PANTHERA”-CTRIAL-IE 17-13 [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 OT3-06-01.

Background The ASCO/CAP guidance on HER2 testing in breast cancer (BC) has recently changed. Group 2 tumours with immunohistochemistry score 2+ and HER2/CEP17 ratio ≥2.0 and HER2 copy number Methods 749 BC cases were identified from 11 institutions. The association between HER2 groups and pathological complete response (pCR) was assessed. Results 54% of immunohistochemistry HER2 positive (score 3+) BCs showed pCR, compared to 19% of immunohistochemistry 2+ FISH amplified cases. 27% of Group 2 treated with HER2 targeted therapy achieved pCR, compared to 19 and 11% in the combined Groups 1 + 3 and Groups 4 + 5, respectively. No difference in pCR rates was identified between Group 2 and Group 1 or combined Groups 1 + 3. However, Group 2 response rate was higher than Groups 4 + 5 (p = 0.017). Conclusion No difference in pCR was detected in tumours with a HER2/CEP17 ratio ≥2.0 and a HER2 score 2+ by IHC when stratified by HER2 gene copy number. Our data suggest that ASCO/CAP HER2 Group 2 carcinomas should be evaluated further with respect to eligibility for HER2 targeted therapy.

Simple Summary Patients with HER-2 positive breast cancer who progress through available HER2-targeted therapy, at present, have few effective treatment options. PIK3CA is mutated in approximately 20% of HER2 positive breast cancers, contributes to HER-2 therapy resistance and may be predictive of response to PI3K inhibitors, including copanlisib. PIK3CA gene mutations were assessed in archival tumour tissue and serially in plasma circulating tumour DNA over the course of treatment with copanlisib. Disease stabilisation (stable disease ≥16 weeks) was seen with copanlisib and trastuzumab in a proportion of participants (n = 6, 50%). PIK3CA mutation detected in archival tumour tissue did not appear to predict tumour response to copanlisib and trastuzumab in this small, heavily pre-treated cohort. Notably, PIK3CA circulating tumour DNA mutations were detected in the plasma of all trial participants, including those who tested negative for the mutation in tissue. This study established a dosing strategy for the novel combination of the PI3K inhibitor copanlisib with trastuzumab and suggested clinical activity for the combination in heavily pre-treated HER-2 positive advanced breast cancer. Further evaluation in a phase 2 study in patients with HER2 therapy resistant tumours is ongoing (NCT02705859). Abstract Background: Activation of the phosphoinositide-3 kinase (PI3K) pathway is a resistance mechanism to anti-human epidermal growth factor receptor 2 (HER2) therapy. This phase Ib trial was conducted to determine the maximum tolerated dose (MTD) of copanlisib, an intravenous (IV) pan-class I PI3K inhibitor, combined with trastuzumab. Methods: Patients with advanced HER2-positive breast cancer and disease progression following at least one prior line of HER2 therapy in the metastatic setting were treated with copanlisib (45 or 60 mg) IV on days 1, 8 and 15 of a 28-day cycle with a fixed dose of trastuzumab 2 mg/kg weekly. Results: Twelve patients were enrolled. The MTD was determined as copanlisib 60 mg plus trastuzumab 2 mg/kg weekly. The most common adverse events of any grade occurring in more than two patients were hyperglycaemia (58%), fatigue (58%), nausea (58%) and hypertension (50%). Stable disease was confirmed at 16 weeks in six participants (50%). PIK3CA mutations were detected in archival tumour of six participants (50%). PIK3CA hotspot mutations, were detectable in pre- and on-treatment plasma of all participants. Pre- and post-treatment tumour biopsies for two patients identified temporal genomic heterogeneity, somatic mutations in the TRRAP gene, which encodes a PI3K-like protein kinase, and emergent somatic mutations related to protein kinase signalling. Conclusion: Copanlisib and trastuzumab can be safely administered with fair overall tolerability. Preliminary evidence of tumour stability was observed in patients with heavily pre-treated, metastatic HER2 positive breast cancer. Several potential biomarkers were identified for further study in the current phase 2 clinical trial. NCT: 02705859.

Background: Systemic anti-cancer treatment (SACT) can improve symptoms and survival in patients with incurable cancer but there may be harmful consequences. Information regarding the use of SACT at the end-of-life and its impact on patients has not been described in Ireland. Aims: The study aimed to quantify and describe the use of SACT at end-of-life. The primary outcome of interest was the number of patients who received treatment in the last 12, 4 and 2 weeks of life. Secondary outcomes included the frequency of admissions and procedures, location of death, and timing of specialist palliative care (SPC) referral. Methods: Retrospective review. Fisher exact testing was used for analyses. Patients were included if they died between January 2015 and July 2017 and received at least 1 dose of treatment for a solid tumor malignancy. Results: Five hundred and eighty two patients were included. Three hundred and thirty eight (58%), 128 (22%) and 36 (6%) received treatment in the last 12, 4 and 2 weeks of life respectively. Patients who received chemotherapy in the last 12 weeks of life were more likely to be admitted to hospital, undergo a procedure, and die in hospital than those who did not (P < 0.001 for all). Median time of SPC referral before death was shorter in those patients who received chemotherapy than those who did not (61 v129 days, p = 0.0001). Conclusion: Patients who received chemotherapy had a higher likelihood of hospital admission, invasive procedure, and in-hospital death. They were less likely to have been referred early to SPC services.

Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. We identified 155 patients—71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I–III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Cancer clinical trials (CCTs) are critical to translation and development of better therapies to improve outcomes. CCTs require adequate patient involvement but accrual rates are low globally. Several known barriers impede participation and knowing how subpopulations differ in understanding of CCTs can foster targeted approaches to aid accrual and advance cancer treatments. We conducted the first nationwide survey of 1089 patients attending 14 Irish cancer centres, assessing understanding of fundamental concepts in CCT methodology and factors that influence participation, to help tailor patient support for accrual to CCTs. Two-thirds (66%) of patients reported never having been offered a CCT and only 5% of those not offered asked to participate. Misunderstanding of clinical equipoise was prevalent. There were differences in understanding of randomisation of treatment by age (p &lt, 0.0001), ethnicity (p = 0.035) and marital status (p = 0.013), and 58% of patients and 61% previous CCT participants thought that their doctor would ensure better treatment in CCTs. Females were slightly more risk averse. Males indicated a greater willingness to participate in novel drug trials (p = 0.001, p = 0.003). The study identified disparities in several demographics, older, widowed, living in provincial small towns and fewer years-educated patients had generally poorer understanding of CCTs, highlighting requirements for targeted support in these groups.

Background & objective: Liver resection for breast cancer liver metastases is becoming a more widely accepted therapeutic option for selected groups of patients. The aim of this study was to describe the outcomes of patients undergoing liver resection for breast cancer-related liver metastases and identify any variables associated with recurrence or survival. Methods: A retrospective review of a prospectively maintained database was undertaken for the 12 year period between 2009 and 2021. Clinicopathological, treatment, intraoperative, recurrence, survival and follow-up data were collected on all patients. Kaplan-Meier methods, the log-rank test and Cox proportional hazards regression analysis were used to identify variables that were associated with recurrence and survival. Results: A total of 20 patients underwent 21 liver resections over the 12-year period. There were no deaths within 30 days of surgery and an operative morbidity occurred in 23.8% of cases. The median local recurrence free survival and disease free survival times were both 50 months, while the 5 year overall survival rate was 65%. The presence of extrahepatic metastases were associated with a decreased time to local recurrence (p Conclusions: This study has demonstrated that liver resection for breast cancer-related liver metastases is feasible, safe and associated with prolonged disease free and overall survival in selected patients. It is likely that this option will be offered to more patients going forward, however, the difficulty lies in selecting out those who will benefit from liver resection particularly given the increasing number of systemic treatments and local ablative methods available that offer good long-term results.

Background: In NSABP B-14, the quantitative levels of ESR1 mRNA, assessed using the standardized 21-gene assay and qRT-PCR platform predicted tamoxifen benefit (interaction p-value 9.1. Recurrence-free interval was a secondary endpoint. Results: The results of the assay were available for 587 patients. The median ER score was 10.2 (IQR 9.3-11.0). There were 131 patients (23.2% weighted) with ER ≤9.1 and 456 (76.8% weighted) with ER >9.1. No significant interaction of the effect of extended letrozole treatment was found for either the ER single gene score (interaction hazard ratio letrozole vs. placebo with an IQR change in ER score 1.10, 95% CI 0.66 - 1.82, p=.72) or the categories ER ≤9.1 (treatment HR=0.40, 95% CI 0.15-1.06) or ER >9.1 (treatment HR=0.70, 95% CI 0.43-1.12) (interaction p=.32). There was also no apparent prognostic effect of the ER single gene score for distant recurrence with placebo treatment after 5 years of endocrine therapy (p=.12). Results were similar in analyses of any recurrence, analyses adjusting for the proliferation axis from the 21-gene assay, and subgroup analyses by nodal and HER2-status. Conclusions: The B-42 study provided no evidence that ESR1 mRNA as measured by the ER single gene score can inform decisions regarding extended letrozole therapy after 5 years of adjuvant endocrine therapy. Confidence intervals were relatively wide but rule out a strong predictive effect of the ER single gene score in the expected direction. Support: U10CA180868, -180822, U24CA196067; Novartis; Exact Sciences Citation Format: Eleftherios Mamounas, Hanna Bandos, Priya Rastogi, Michael R Crager, Carolyn Mies, Peter C Lucas, Charles E Geyer, Jr, Louis Fehrenbacher, Mark L Graham, Stephen KL Chia, Adam M Brufsky, Janice M Walshe, Gamini S Soori, Shaker R Dakhil, Soonmyung Paik, Sandra M Swain, Frederick L Baehner, Steven Shak, Norman Wolmark. Assessment of estrogen receptor (ESR1) mRNA expression for prediction of extended aromatase inhibitor benefit in HR-positive breast cancer using NRG Oncology/NSABP B-42 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD15-05.

Background: The American Joint Commission Cancer (AJCC) Cancer Staging Manual 8th edition introduced a breast cancer (BC) Prognostic Stage (PS) that combines tumour grade, oestrogen (ER), progesterone (PgR), and human epidermal growth factor-2 (HER2) receptor status with Anatomic TNM Stage (AS). In a further modification, patients with early BC and an Oncotype DX® Recurrence Score (RS) < 11 are assigned to PS 1A irrespective of grade and size up to 5 cm. This study profiles the impact of these changes on staging in patients with early BC and RS < 11. Methods: A total of 127 patients, with primary BC and RS < 11, were identified from a consecutive series of 729 patients with ER-positive, HER2-negative, lymph node-negative, primary BC whose tumours were tested using the Oncotype DX® 21 multigene assay. Each patient was assigned AS, PS, and RS-modified PS, and staging categories were compared. Results: Applying AS, 100 patients were stage IA and 27 IIA. Applying PS, 89 were stage IA, 33 IB, 4 IIA, and 1 IIB. All patients were IA according to RS-modified PS. Comparing PS to AS, 26.7% of patients (n = 34) changed stage, 9.4% (n = 12) to a higher and 17.3% (n = 22) to a lower stage. RS-modified PS versus AS resulted in downstaging in 21.3% (n = 27). Comparing PS modified by RS to PS alone, 29.9% (n = 38) were downstaged. Conclusion: Application of PS and RS-modified PS results in tumour downstaging in approximately 20% of patients with early BC. Upstaging was observed in 9% of patients when staged according to PS and was primarily due to the impact of high histological grade.

Background The optimal timing of (neo)adjuvant trastuzumab initiation with respect to chemotherapy and surgery remains undefined. Methods Retrospective analysis of a large institutional database of HER2-positive patients who received anti-HER2 therapy. We included all Stage I to III patients treated with trastuzumab with a minimum follow up of 3 years. The date of first breast biopsy was recorded as initial diagnosis. Results A total of 506 patients [adjuvant: 386 (76%)-neo-adjuvant: 120 (24%)] were included. The median time-to-first-trastuzumab (TFT) from diagnosis was 12 weeks (range 1.9–122.3). Median follow-up is 73.3 months (range 1.4–176.3). TFT was significantly shorter in the neo-adjuvant than in the adjuvant cohort (median: 4.4 vs. 14 weeks, p 12 weeks. Early concomitant regimens were associated with superior DFS over delayed-concomitant and sequential regimens. Conclusions Initiating trastuzumab more than 12 weeks from diagnosis has a negative impact on clinical outcome. Neo-adjuvant anti-HER2 therapy could be the optimal strategy to treat early stage HER2-positive breast cancer.

Young women with breast cancer (YWBC) represent 7–12% of breast cancer diagnoses and ostensibly have more biologically aggressive subtypes with higher relapse and mortality rates. We studied the clinical and pathological characteristics in YWBC and examined how outcomes and treatment have evolved. YWBC were identified from pathology databases at two tertiary centers. Patients were divided into two cohorts: those diagnosed from 2000 to 2005 (C1) and from 2006 to 2015 (C2). Data were retrieved from clinical, radiology, and histology databases. Statistical analysis was performed using R® (V3.2.0). We identified 345 patients. Median age was 36 years (23–39 years). Mastectomy was performed in 232 patients (67.2%) and axillary lymph node clearance (ALNC) in 207 patients (60% [C1 82.7 vs. C2: 49.4%, p

Background Trastuzumab (T) administered for 12 months (mos) as part of a taxane (Tax)– or Tax+anthracycline (Anthra)–based AdjTx is the standard of care as (neo)AdjTx of HER2+ ESBrCa. Several prospective randomized trials have investigated a shorter duration of Adj T (i.e. 9 weeks or 6 mos) compared to standard 12 mos of T. However, the results have not been conclusive so far. The impact of administering non-Tax/non-Anthra-based AdjTx and single-agent T on long-term outcome of HER2+ ESBrCa is not fully known. Methods We conducted a retrospective analysis on a prospectively maintained departmental database of all patients (pts) with Stage I-III HER2+ ESBrCa treated with at least one dose of (neo)Adj T. Pre-planned duration of T was 12 mos for all pts. TTE was defined as the interval in weeks between the first and the last dose of T. In order to ensure that most pts had a minimum FU of 3 yrs we included all pts who received 1st T before March 31st 2014. The database was locked for outcome analyses on March 31st 2017. Results 506 pts treated between October 2001 and March 2014 were included in the study. Main pts characteristics: median age: 55 years (range: 26-85), oestrogen (ER) and/or progesterone (PR) receptors positive: 321 (63%), axillary lymph nodes positive: 266 (52%), Adj T: 386 (76%), neoAdj T: 120 (24%), Tax- and Tax/Anthra–based AdjTx: 457 (90%), non-Tax/non-Anthra AdjTx and single-agent T (without chemotherapy): 49 (10%). Median FU is 73.3 months (range: 1.4-176.3). In the overall population, DFS and OS rates are 83% and 91%, respectively. Pts treated with non-Tax/non-Anthra AdjTx had a significantly higher risk of BrCa relapse [DFS: HR 3.54 (95%CI:1.24 to 10.06, p=0.018)], and death [OS: HR 2.73 (95%CI:0.63 to 11.77 p=0.176)] compared to those treated with Tax–based AdjTx (e.g. TCH [docetaxel/carboplatin/T]). Pts who received single-agent T also had highly significantly worse DFS [HR 4.21 (95%CI:2.18 to 8.38, p55 yrs), the detrimental impact of type of AdjTx remained highly statistically significant (p24weeks. In most cases, shorter duration of T was due to reduction in LVEF or patients refusal. In the multivariate model, positive lymph nodes, type of (neo)AdjTx and TET (24 weeks) remained all significant and independent variables associated with worse DFS and OS. Conclusions Our mature results indicate that the administration of non-Tax/non-Anthra-based AdjTx and single-agent T is associated with a significant increase in the risk of disease relapse and death and should not be considered as therapeutic options for pts with HER2+ ESBrCa. The administration of T for Citation Format: Gullo G, Walsh N, Fennelly D, Walshe J, O'Mahony K, Silva N, Ballot J, Calzaferri G, Quinn C, McDonnell D, Crown J. Impact of type of (neo)adjuvant systemic therapy (AdjTx) and total exposure to trastuzumab (TET) on long-term outcome of HER2-positive (HER2+) early stage breast cancer (ESBrCa) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-05.

BACKGROUND: Previous findings from the PALOMA-2 study (N=666) demonstrated the efficacy and safety of PAL+LET as first-line ABC therapy versus placebo (PBO)+LET (Finn et al, NEJM. 2016). This analysis evaluated the efficacy and safety of PAL+LET by geographic region (North America [NA], Europe [EU], and Asia Pacific [AP]; data cutoff: Feb 26, 2016). METHODS: Women with ER+/HER2– ABC who had not received prior systemic treatment in the advanced setting were randomized 2:1 to PAL (125 mg/d oral [3 wks on, 1 wk off])+LET (2.5 mg once daily) or PBO+LET. RESULTS: This analysis included 267 patients from NA, 307 from EU, and 92 from AP. At baseline, demographics and disease characteristics generally were similar between regions. In the overall population (Table 1), PAL+LET demonstrated improvements versus PBO+LET in progression-free survival (PFS), objective response rate (ORR), and clinical benefit response rate (CBR). Similarly, PFS was longer and ORR and CBR were higher with PAL+LET versus PBO+LET in NA, EU, and AP subgroups (Table 1). All-grade treatment-emergent adverse events (AEs) (PAL+LET/PBO+LET) occurred in 99%/99% of patients in NA, 98%/92% in EU, and 100%/96% in AP. In the PAL+LET arm, neutropenia (all-grade/grade ≥3) was the most common AE in all regions. The incidence of neutropenia was numerically higher in AP (91%/84%) compared with NA (73%/65%) and EU (81%/62%). Grade 3 or 4 febrile neutropenia occurred in 4 (2%) NA patients, 4 (2%) EU patients, and no AP patients in the PAL+LET arm and in no patients in any of the regions in the PBO+LET arm. CONCLUSIONS: PAL+LET showed improvement versus PBO+LET in PFS, ORR, and CBR in patients with ER+/HER2- ABC in NA, EU, and AP, with comparable magnitude of benefit between regions. With PAL+LET, neutropenia was the most commonly reported AE in all regions, with a numerically higher incidence reported in AP versus NA or EU; the safety profile was similar to previously reported results in the overall population. Funding: Pfizer (NCT01740427) section, copy and paste the following tag, including brackets, where you would like your table to appear Table 1. PFS, ORR, and CBR Median PFSPFS HRORR,* %CBR,* % (95% CI), mo(95% CI)(95% CI)(95% CI)Overall Population PAL+LET24.8 (22.1-NE)0.58 (0.46-0.72); P . Citation Format: Gelmon KA, Castrellon A, Joy AA, Walshe JM, Ettl J, Mukai H, Park IH, Lu DR, Mori A, Bananis E, Diéras V, Finn RS. Efficacy and safety of palbociclib (PAL) + letrozole (LET) as first-line therapy in estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC): Findings by geographic region from PALOMA-2 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-25.

Background: The randomized phase II SNAP trial assessed three alternative reduced maintenance chemotherapy regimens using nab-Paclitaxel after a short term induction phase at conventional doses as first line treatment in patients (pts) with metastatic breast cancer (MBC). For all three regimens median progression-free survival was greater than achieved with full dose docetaxel (historical reference). Symptom palliation and quality of life (QoL) are important when deciding on therapeutic agents and schedules in MBC pts. Methods: Of the 258 pts with MBC enrolled from April 2013 to August 2015 in the SNAP trial, 255 were included in the QoL analysis. Pts were randomized to three arms, each receiving the same induction chemotherapy based on 3 cycles of nab-Paclitaxel 150 mg/m2 dd 1, 8, 15 Q28, which was reduced to 125 mg/m2 after a safety review. The schedules of nab-Paclitaxel in maintenance therapy differed in each arm: Arm A) 150 mg/m2 dd 1,15 Q28; Arm B) 100 mg/m2 dd 1,8,15 Q28; Arm C) 75 mg/m2 dd 1,8,15,22 Q28. Pts completed a QoL form to assess global and symptom-specific indicators (range 0-100) at baseline, and at day 1 of every cycle for the first 12 cycles on treatment, or until treatment discontinuation. Changes in QoL scores during induction (day 1 cycle 4 − baseline) and maintenance (day 1 cycle 12 – day 1 cycle 4) therapy were summarized descriptively per arm. Treatment effects on changes in QoL during maintenance therapy were analyzed by repeated measurement models including timepoints (from day 1 of cycle 4 to day 1 of cycle 12), induction start dose, age, and treatment arms as covariates. Results: During induction therapy, mean changes [SD] in hair loss (Arm A:−70.2 [41.9]; Arm B: −77.3 [34.5]; Arm C: −72.6 [32.8]), sensory neuropathy (Arm A: −19.0 [25.2]; Arm B: −20.6 [22.7]; Arm C: −18.8 [23.8]), and treatment burden (Arm A: −12.9 [33.4]; Arm B: −13.4 [33.5]; Arm C: −11.4 [34.8]) showed the most pronounced worsening. During maintenance therapy, scores for sensory neuropathy remained impaired without worsening. No significant differences in changes for sensory neuropathy or the other symptoms were seen between arms, except for hair loss, with pts in arm C (mean difference 10.91; 95% CI [0.35, 21.48]; p=0.04) ] and B (mean difference 18.55; 95% CI [7.52, 29.59]; p=0.001) reporting a greater improvement compared to those in arm A. Pts in arm C reported a significantly greater improvement in mood compared to arm A (mean difference 13.34; 95% CI [6.08, 20.60]; p Conclusion: The effectiveness of alternative maintenance chemotherapy schedules with reduced doses after a short term induction phase at conventional doses must be weighed against a substantial worsening in sensory neuropathy during induction therapy, and scores continuing to be impaired without worsening with prolonged administration. During maintenance therapy, improvements were seen in the perception of hair loss and in mood, particularly in Arm B and C, with a similar tendency seen for some other QoL domains. A more frequent administration of reduced dose chemotherapy agents is favorable with respect to QoL in this setting. Citation Format: Ribi K, Sun Z, Jerusalem G, Hasler-Strub U, Colleoni M, von Moos R, Cortés J, Vidal M, Hennessy B, Walshe J, Amillano Parraga K, Morales Muriilo S, Pagani O, Barbeaux A, Bortsnar S, Maibach R, Regan MM, Gennari A, Bernhard J. Nab-Paclitaxel-based therapy in the first line treatment of metastatic breast cancer (IBCSG 42-12/BIG 2-12 SNAP): Impact of different schedules on quality of life [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-18-02.

Background The phosphoinositide 3 kinase (PI3K) pathway is important in the oncogenic function of HER2. Aberrent activation of PI3K is implicated in resistance to trastuzumab and other HER2-targeted therapies and is frequent, with up to 22% of HER2 positive breast cancer having a PIK3CA mutation. Copanlisib is a pan-class 1 PI3K inhibitor that shows particular activity against PI3Kα, the isoform encoded by the PIK3CA gene. Copanlisib has been shown to re-sensitise trastuzumab resistant cell lines to trastuzumab with synergism seen in some cell lines between copanlisib and HER2 targeted therapy. Trial design The study is a phase Ib/II open label, single arm adaptive, multi-centre trial of copanlisib in combination with trastuzumab. Eligible patients are treated with a dose escalation schedule of copanlisib IV on Days 1, 8 and 15 of a 28 day cycle with trastuzumab 2 mg/kg weekly (loading dose of 4 mg/kg in cycle 1). The phase II dose will be based on the maximum tolerated dose (MTD) established in Phase Ib. Patients are treated until radiologic or symptomatic progression, unacceptable toxicity, consent withdrawal or physician's decision. Eligibility criteria Eligible patients must have recurrent incurable or metastatic HER2-positive breast cancer that has progressed on at least one prior line of trastuzumab or T-DM1-based treatment regimen in this setting. Patients with treated and controlled brain metastases are eligible. Participants must have adequate organ function and ECOG PS ≤ 2. Patients recruited for the Phase II part of the study must have a PIK3CA mutation. Patients with uncontrolled arterial hypertension, uncontrolled diabetes or recent clinically serious infections are excluded. Specific aims The primary end point for the phase Ib part of this study is to determine the MTD for the combination. For the phase II study is anti-tumour efficacy, measured by Clinical Benefit Rate (CBR). Secondary end points are evaluation of safety and tolerability, progression-free survival, time to treatment failure, duration of response and overall survival. Incorporated translational endpoints include examination of molecular tumor adaptation in tissue and blood. Given the role of PI3K in cellular glucose metabolism, an additional exploratory objective is to determine if quantitive reduction in metabolic signal on Positron Emission Tomography-Computed Tomography (PET-CT) is predictive of benefit from therapy. Statistical methods To establish the MTD, we use a modified 3+3 design where 3 additional patients will be accrued even if the first 3 patients accrued experience no dose limiting toxicities (DLT) in sequential cohorts for a planned 12 patients. To determine the CBR, a one sample exact binomial test with a one sided significance level of 5%, 19 evaluable patients will provide >80% power to detect a difference between the null hypothesis proportion of 30% for CBR versus the alternative hypothesis proportion of 65%. Present accrual and target accrual There are 9 patients recruited so far to the phase Ib part of this study. Target accrual is 12 and for phase II is 19 patients. Contact information for people with a specific interest in the trial Prof Bryan Hennessy, Beaumont Hospital, Dublin Ireland Funded by Bayer Citation Format: Keegan NM, Walshe J, Gullo G, Kennedy J, Bulger K, Kelly CM, Crown J, Toomey S, Egan K, Kerr J, Given M, Hernando A, Teiserskiene A, Grogan L, Breathnach O, Morris PG, Keane M, Hennessy BT. A phase Ib/II trial of coPANlisib in combination with tratuzumab in pretreated recurrent or metastatic HER2-positive breast cancer “PantHER” [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-06-05.

BACKGROUND: Palbociclib plus letrozole significantly improved progression-free survival (PFS) compared with letrozole plus placebo in treatment-naive postmenopausal patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in the phase 3 PALOMA-2 trial. Here, we compare patient-reported general health status with extended (max 53 cycles) follow-up (data cut off May31st, 2017) (Pfizer: NCT01740427). METHODS: PALOMA-2 randomized patients 2:1 to palbociclib + letrozole (n=444) or placebo + letrozole (n=222). Patient-reported outcomes were assessed at baseline, day 1 of cycles 1, 2, and 3, and day 1 of every other cycle from cycle 5 until the end of treatment using the EuroQol 5-Dimension Questionnaire (EQ-5D). The EQ-5D is a standardized measure of health status that consists of a descriptive system comprising the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression rated at 3 levels (no, some, or extreme problems) and a single index score for health status (ranges generally from 0 [dead] to 1 [full health]) calculated using a standard algorithm. In addition, a visual analog scale (VAS) measured self-rated health status from 0 (worst imaginable) to 100 (best imaginable). Repeated measures mixed-effects analyses were performed to compare overall index and VAS scores between treatments, controlling for baseline. RESULTS: Completion rates at baseline were >95% in each group. The mean (SD) scores at baseline were comparable between palbociclib plus letrozole and letrozole alone for the VAS (71.3 [21.2] vs 72.3 [19.8]) and the EQ-5D index scores (0.70 [0.25]) vs (0.73 [0.21]). Median follow up was 38 months for palbociclib plus letrozole and 37 months for letrozole only. No statistically significant difference in overall change from baseline in general health status was observed between the treatment arms. The proportion of patients reporting the presence of a problem at baseline was similar for palbociclib plus letrozole and letrozole, respectively: mobility (39% vs 39%), self-care (12% vs 12%), usual activities (44% vs 39%), pain (69% vs 65%), and anxiety/depression (54% vs 54%). No statistically significant difference in overall mean EQ-5D index scores (0.73 vs. 0.71) was observed between the treatment arms. CONCLUSION: Addition of palbociclib to letrozole maintained general health status and EQ-5D index scores in ER+ HER2- advanced/metastatic breast cancer with no statistically significant differences observed compared to letrozole alone. Citation Format: Harbeck N, Dieras V, Finn R, Gelmon KA, Walshe JM, Shparyk Y, Mori A, Lui DR, Bhattacharyya H, Iyer S, Johnston S, Rugo HS. Impact of palbociclib plus letrozole on patient-reported general health status compared with letrozole alone in ER+/HER2- advanced/metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-19-01.

Oncotype DX® is a gene expression assay that quantifies the risk of distant recurrence in patients with hormone receptor positive early breast cancer, publicly funded in Ireland since 2011. The aim of this study was to correlate Oncotype DX® risk groupings with traditional histopathological parameters and the results of other risk assessment tools including Recurrence Score-Pathology-Clinical (RSPC), Adjuvant Risk Index (Adj RI), Nottingham Prognostic Index (NPI) and the Adjuvant! Online 10-year score (AO). Patients were retrospectively identified from the histopathology databases of two Irish hospitals and patient and tumour characteristics collated. Associations between categorical variables were evaluated with Pearson's chi-square test. Correlations were calculated using Spearman's correlation coefficient and concordance using Lin's concordance correlation coefficient. Statistical analysis was performed using SPSS software, version 22.0.In our 300 patient cohort, Oncotype DX® classified 59.7% (n = 179) as low, 30% (n = 90) as intermediate, and 10.3% (n = 31) as high risk. Overall concordance between the RS and RSPC, Adj RI, NPI, and AO was 67.3% (n = 202), 56.3% (n = 169), 59% (n = 177), and 36.3% (n = 109), respectively. All risk assessment tools classified the majority of patients as low risk apart from the AO 10-year score, with RSPC classifying the highest number of patients as low risk. This study demonstrates that there is good correlation between the RS and scores obtained using alternative risk tools. Concordance with NPI is strong, particularly in the low-risk group. NPI, calculated from traditional clinicopathological characteristics, is a reliable alternative to Oncotype DX® in the identification of low-risk patients who may avoid adjuvant chemotherapy.

Background Longer chemotherapy (CT) duration is associated with a significant improvement in progression-free survival (PFS) and a moderate, but significant improvement in overall survival (OS) in MBC patients (pts). Prolonged CT administration, however, must be weighed against the side effects of continuous CT delivery. The SNAP trial was designed to improve the tolerability of prolonged CT by studying alternative treatment schedules. Methods The SNAP trial enrolled 258 women from April 2013 to Aug 2015. Eligibility criteria included HER2- MBC, no prior CT for advanced disease, measurable and/or non-measurable disease. All eligible pts were randomized to one of three arms. Pts received the same induction chemotherapy consisting of 3 cycles of nab-Paclitaxel given days 1,8,15 Q28, followed by one of the three maintenance therapy schedules. Originally, the dose of the induction chemotherapy was 150 mg/m2, but this was reduced to 125 mg/m2 following the first safety review of 48 treated pts. The three schedules of nab-Paclitaxel used as maintenance therapy were (Arm A) nab-Paclitaxel 150 mg/m2 d 1,15 Q28; (Arm B) nab-Paclitaxel 100 mg/m2 d 1,8,15 Q28; (Arm C) nab-Paclitaxel 75 mg/m2 d 1,8,15,22 Q28. The primary objective is to evaluate the efficacy of three nab-Paclitaxel regimens as measured by progression-free survival (PFS), using the historical reference of PFS (based on AVADO study) of docetaxel for first-line treatment of metastatic breast cancer. Each of the three regimens is compared to the historic 7-month median PFS to determine whether any of the three regimens are worthy of further investigation. Secondary endpoints include tolerability, feasibility, response rate, OS and QoL. Results Two-hundred-fifty-eight pts have been randomised and 255 are available for primary endpoint evaluation. At 18.2 months' median follow-up, 182 PFS events and 85 deaths have been observed. Median PFS was 7.9 months (90%CI 6.8-8.4) in Arm A, 9.0 months (90%CI 8.1-10.9) in Arm B and 8.5 (90%CI 6.7-9.5) in Arm C. PFS in Arm B was significantly longer than the historic PFS of first-line docetaxel (one-sided log-rank p=0.03). As expected, neurotoxicity was the most frequent adverse event. In the induction phase, grade≥2 sensory neuropathy was reported in 14.8% of pts at the starting dose of 150 mg/m2 and 7.5% at the starting dose of 125 mg/m2; grade≥3 sensory neuropathy occurred in 2.5% and 0% of the pts, respectively. In the maintenance phase, grade≥2 sensory neuropathy was reported in 37.9% of pts in Arm A, 36.1% in Arm B and 31.2% in Arm C; grade≥3 sensory neuropathy occurred in 9.1%, 5.6% and 6.6% of the pts, respectively. 199 pts started the maintenance phase. The median number of maintenance cycles was 3, 4, and 5, respectively. Stopping maintenance for reasons other than objective progression occurred in 41%, 58%, and 53%, respectively. Conclusion The SNAP trial indicates that alternative maintenance chemotherapy schedules with reduced doses after a short term induction phase at conventional doses are feasible and significantly more active than the historical PFS of docetaxel in the first line treatment of advanced breast cancer. Citation Format: Gennari A, Sun Z, Hasler-Strub U, Colleoni M, Kennedy J, von Moos R, Cortes J, Vidal M, Hennessy B, Walshe J, Amillano Parraga K, Morales Murrillo S, Pagani O, Barbeaux A, Borstnar S, Rabaglio M, Maibach R, Regan MM, Jerusalem G. Randomized phase II study evaluating different schedules of nab-paclitaxel in metastatic breast cancer (MBC): Results of the SNAP study [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 P5-15-05.

Background: Combining bevacizumab and chemotherapy produced superior response rates compared with chemotherapy alone in metastatic breast cancer. As bevacizumab may cause hypertension (HTN) and increase the risk of cardiac failure, we performed a pilot study to evaluate the feasibility and toxicity of a non-anthracycline-containing combination of docetaxel with cyclophosphamide and bevacizumab in early stage breast cancer patients. Methods: Treatment consisted of four 3-weekly cycles of docetaxel and cyclophosphamide (75/600 mg/m2). Bevacizumab was administered 15 mg/kg intravenously on day 1, and then every 3 weeks to a total of 18 cycles of treatment. Serum biomarker concentrations of vascular endothelial growth factor (VEGF), cardiac troponin-I (cTnI), myeloperoxidase (MPO), and placental growth factor (PlGF) were quantified using enzyme-linked immunosorbent assay (ELISA) in 62 patients at baseline and whilst on treatment to determine their utility as biomarkers of cardiotoxicity, indicated by left ventricular ejection fraction (LVEF). Results: A total of 106 patients were accrued in nine sites. Median follow up was 65 months (1–72 months). Seventeen protocol-defined relapse events were observed, accounting for an overall disease-free survival (DFS) rate of 84%. The DFS rates for hormone receptor positive (HR+) and triple-negative (TN) patients were 95% versus 43%, respectively. The median time to relapse was 25 (12–54) months in TN patients versus 38 (22–71) months in HR+ patients. There have been 13 deaths related to breast cancer . The overall survival (OS) rate was 88%. The 5-year OS rate in HR+ versus TN was 95% versus 57%. None of the measured biomarkers predicted the development of cardiotoxicity. Conclusions: We observed a low relapse rate in node-positive, HR+ patients; however, results in TN breast cancer were less encouraging. Given the negative results of three large phase III trials, it is unlikely that this approach will be investigated further. Trial Registration ClinicalTrials.gov Identifier: NCT00911716.

502 Background: The 70-gene MammaPrint (MP) assay predicts risk of distant recurrence (DR) in hormone-receptor positive early-stage breast cancer and classifies cancers as Low Risk or High Risk. NSABP B-42 evaluated ELT in patients (pts) who had completed 5 yrs of adjuvant endocrine therapy (tx). The primary objective was to determine the utility of MP to identify pts enrolled in NSABP B-42 who are likely to benefit from ELT. Methods: A total of 1,866 pts from B-42 had available MP results. Primary endpoint is DR. Secondary endpoints are disease-free survival (DFS) and breast cancer-free interval (BCFI). For the primary analysis, pts were classified as High Risk (MP-H) (MP score ≤0.000) or Low Risk (MP-L) (MP score > 0.000). Exploratory analyses were performed for MP-L subcategories: MP Ultralow Risk (MP-UL) (MP score > 0.355) and MP-L but not MP-UL (MP-LNUL) (MP score > 0.000, ≤0.355). Likelihood ratio test based on stratified Cox proportional hazards (PH) model was used for treatment by risk group interaction. Stratified log-rank test was used to compare treatment groups. Hazard ratios and 95% CI were computed based on the stratified Cox PH model. Results: Among 1,866 pts, 706 (38%) were MP-H and 1,160 (62%) were MP-L. Of the MP-L, 252 (22%) were MP-UL. There were no significant differences in the distribution of patient and tumor characteristics between the MP group and the rest of the B-42 cohort, except for HER2 status. ELT effect was more pronounced in the MP cohort than in the overall B-42 population. For DR, there was statistically significant ELT benefit in MP-L (HR = 0.43, 95% CI 0.25-0.74, p = 0.002), but not MP-H (HR = 0.65, 0.34-1.24, p = 0.19) (interaction p = 0.38). For DFS, there was statistically significant ELT benefit in MP-L, but not MP-H (interaction p = 0.015). Similar findings were observed for BCFI (interaction p = 0.006). Within subcategories of MP-L, there was statistically significant ELT benefit in MP-LNUL, but not in MP-UL for all three endpoints, however the power in MP-UL was limited due to low number of pts (Table). Clinical trial information: 00382070. Conclusions: Statistically significant ELT benefit was observed for MP-L, but not MP-H. The treatment by risk group interaction was not statistically significant for DR, but it was for DFS and BCFI. The benefit appears to be stronger in MP-LNUL than in MP-UL. NCT: 00382070. Support: U10CA180868, -180822, U24CA196067; Novartis; Agendia.[Table: see text]

501 Background: The BCI HOXB13/IL17BR ratio (BCI-H/I) has been shown to predict endocrine tx (ET) and extended ET (EET) benefit. We examined the effect of BCI-H/I for EET benefit prediction in NSABP B-42, evaluating extended letrozole tx (ELT) in HR+ breast cancer patients (pts) who completed 5 yrs of ET. Methods: All pts with available primary tumor tissue were eligible. Primary endpoint was recurrence-free interval (RFI). Secondary endpoints were distant recurrence (DR), breast cancer-free interval (BCFI), and disease-free survival (DFS). Stratified Cox proportional hazards model was used. Due to a non-proportional effect of ELT on DR, time-dependent secondary analyses (≤4y, >4y) were performed. Likelihood ratio test evaluated treatment by BCI-H/I interaction. Results: In 2,179 pts analyzed (60% N0; 62% AI only; 80% HER2-), 45% were BCI-H/I-High and 55% BCI-H/I-Low. ELT showed an absolute 10y benefit of 1.6% for RFI (HR=0.77, 95% CI 0.57-1.05, p=0.10) (BCI-H/I-Low: 1.1% [HR=0.69, 0.43-1.11, p=0.13]; BCI-H/I-High: 2.4% [HR=0.83, 0.55-1.26, p=0.38]; interaction p=0.55). There was no statistically significant ELT by BCI-H/I interaction for BCFI (BCI-H/I-Low: HR=0.53, 0.36-0.78, p=0.001; BCI-H/I-High: HR=0.85, 0.60-1.21, p=0.36; interaction p=0.07) or for DFS (BCI-H/I-Low: HR=0.75, 0.58-0.95, p=0.017; BCI-H/I-High: HR=0.81, 0.64-1.04, p=0.09; interaction p=0.62). Before 4y, there was no statistically significant ELT benefit on DR in either BCI-H/I group. After 4y, BCI-H/I-High pts had statistically significant ELT benefit on DR (HR: 0.29, 0.12-0.69, p=0.003), while BCI-H/I-Low pts were less likely to benefit (HR: 0.68, 0.33-1.39, p=0.28) (interaction p=0.14). Conclusions: BCI-H/I prediction of ELT benefit on RFI was not confirmed. In time-dependent DR analyses, BCI-H/I-High pts had statistically significant benefit from ELT after 4y, while BCI-H/I-Low pts did not. Observed ELT benefit on BCFI in BCI-H/I-Low pts was primarily driven by second primary breast cancers. Additional follow-up is needed to further characterize BCI-H/I predictive ability in this study. Support: U10CA180868, -180822, U24CA196067; Novartis; Biotheranostics. Clinical trial information: NCT00382070. [Table: see text]

510 Background: Trastuzumab (T) increases the incidence of cardiac events (CEs) in patients (pts) with early breast cancer (BC). Dual blockade with P+T improves BC outcomes and is the standard of care for high-risk HER2-positive BC pts following the phase 3 APHINITY trial that evaluated the addition of P or placebo (Pla) to T and chemotherapy (CT). We analyzed the cardiac safety of P+T in APHINITY. Methods: APHINITY eligibility required a left ventricular ejection fraction (LVEF) ≥55% at study entry. LVEF assessment was performed every 3 months (mos) during treatment, every 6 mos up to month 36, and yearly thereafter. Primary CE was defined as heart failure (HF) class III/IV and a significant decrease in LVEF of at least 10 percentage points from baseline and to

Doxorubicin (Dox), a mainstay of adjuvant breast cancer treatment, is associated with cardiac toxicity in the form of left ventricular dysfunction (LVD), LV diastolic dysfunction, or LV systolic dysfunction. Study objectives were to evaluate the prevalence of LVD in long-term breast cancer survivors treated with Dox and determine if brain-type natriuretic peptide (BNP) may help identify patients at risk for LVD. Patients who participated in prospective clinical trials of adjuvant Dox-based chemotherapy for breast cancer with a baseline left ventricular (LV) ejection fraction evaluation from 1999 to 2006 were retrospectively identified from the St Vincent's University Hospital database. Patients were invited to undergo transthoracic echocardiography, BNP analysis, and cardiovascular (CV) risk factor assessment. LVDD was defined as left atrial volume index34 mL/m(2) and/or lateral wall E prime10 m/s, and LVSD as LVEF50 %. Of 212 patients identified, 154 participated, 19 patients had died (no cardiac deaths), and 39 declined. Mean age was 60.7 [55:67] years. A majority of the patients (128, 83 %) had low CV risk (0/1 risk factors), 21 (13.6 %) had 2 RFs, and 5 (3.2 %) ≥3 RFs. BMI was 27.2 ± 4.9 kg/m(2). Median Dox dose was 240 mg/m(2) [225-298]; 92 patients (59.7 %) received ≤240 mg/m(2) and 62 (40.3 %)240 mg/m(2). Baseline LVEF was 68.2 ± 8 %. At follow-up of 10.8 ± 2.2 years, LVEF was 64.4 ± 6 %. Three (1.9 %) subjects had LVEF50 % and one (0.7 %) had LVDD. Dox240 mg/m2 was associated with any LVEF drop. BNP levels at follow-up were 20.3 pg/ml [9.9-36.5] and 21.1 pg/ml [9.8-37.7] in those without LVD and 61.5 pg/ml [50-68.4] in those with LVD (p = 0.04). Long-term prospective data describing the impact of Dox on cardiotoxicity are sparse. At over 10 years of follow-up, decreases in LVEF are common, and dose related, but LVD as defined is infrequent (2.6 %). Monitoring with BNP for subclinical LVD needs further evaluation.

Background. We have previously reported that ChemoT produces durable (>5 years) CR in a minority of pts with H+MBC, prompting a search for predictive markers. Extensive lymphocytic infiltration of cancers is correlated with high levels of immune gene signatures. International consensus guidelines on TILs define "lymphocyte-predominant BC" at a threshold of S-TILs of 50-60% versus tumour cells. High levels of S-TILs has been correlated with improved outcome in HER2+ early stage BC pts treated with ChemoT. We investigated the degree of S-TIL infiltration in metastatic biopsies from pts with HER2+MBC prior to ChemoT, and attempted to determine whether S-TILs predicted CR in HER2+MBC. Methods. We searched a database of all pts with HER2+ MBC treated at our institution with anti-HER2 therapy over 15yrs to identify pts who achieved CR according to RECIST 1.0 criteria, which lasted for at least 6 months. We matched them with an equal number of pts from the database who were treated during the same period, but who had progressive (POD) or stable disease (SD) as best response to T. Pts must have at least one pre-treatment tumour sample available for S-TILs assessment, and adequate clinical and follow-up information. S-TILs (mononuclear cells including lymphocytes and plasma cells) contained within the boundaries of invasive tumour were identified on a representative haematoxylin and eosin stained slide and scored as a percentage of the stromal area alone, according to the International TILs Working Group 2014 methodology [Salgado R, 2015]. S-TILs were assessed specifically for this study by a senior pathologist who scored the samples and who was blinded to pts response and clinical details. Results. Out of 246 MBC pts registered in the HER2+ database we identified 31 CR pts with at least one available pre-treatment metastatic sample. A cohort of 31 matching POD-SD pts was randomly obtained from the same database. In 8 cases (7 CR / 1 POD-SD) S-TILs could not be assessed due to inadequate material, or for other technical reasons. The final study sample is 54 pts (24 CR / 30 POD-SD). Pts characteristics are as follows: median age (range): CR 55 (29-78) / POD-SD 56 (26-89), hormone receptor (HR) pos: CR 12 (50%) / POD-SD 18 (60%), De Novo MBC at diagnosis: CR 13 (54%) / POD-SD 8 (27%) [p50% were statistically significantly more frequent in CR (50% of pts) than POD/SD (20%) [chi-square p=0.02]. No statistically significant difference in the HR status was observed between the two groups (CR vs POD-SD) or between the high and low S-TILs pts. Conclusions. S-TILs >50% in the pre-treatment tumour biopsy of HER2+MBC were significantly correlated with subsequent CR to ChemoT, supporting the hypothesis that the immunological effects of T may play a role in determining response. Speculatively, S-TILs might identify pts with a higher likelihood of benefit from T. Further study of the potential role of S-TILs as predictors of T benefit are required. Citation Format: Gullo G, Quinn C, Zacchia A, Fennelly D, Defrein A, Ballot J, Zanoni D, Walshe J, Maltese M, McDermott E, Crown J. Pre-treatment stromal tumour-infiltrating lymphocytes (S-TILs) are correlated with complete response (CR) to chemotherapy (Chemo) plus trastuzumab (T) in HER2-positive (H+) metastatic breast cancer (MBC). [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 P4-14-15.

Background. H+BC is an aggressive variant of BC with earlier and more frequent metastatic relapse than HER2 normal disease. Following the reports in 2005 of several large random assignment trials which showed that the anti-HER2 monoclonal antibody T improved the outcome of pts with H+ESBC receiving chemotherapy, we introduced Trastuzumab (T) as a routine component of standard adjuvant (AdjRx) and neo-adjuvant (NAdjRx) therapy for all pts with H+ESBC at our institution. Others had received it investigationally from 2000-2004. We report our 14 year experience with Adj and NAdjRx with T. Methods. We compiled a comprehensive database of all patients ever treated at our institution with Adj or neo-Adj T for H+ESBC. All pts were cross-checked through the Pathology, Pharmacy and Med Onc datasets, and all cases were individually reviewed. Results. Out of 764 pts included in the H+BC medical oncology database, we identified 518 pts (AdjT=373, NAdjT=145) with stage I-III disease treated with T between August 2000 and October 2014. Pts characteristics: median (range) age: 54 (26-86) yrs, hormone-receptor (HR) status: HR positive (HR+) 64%/HR negative (HR-) 35%/HR unknown 1%, lymph node positive (LN+): 52% (AdjT: 44%/NAdjT 72%), systemic therapy+T: TCH [docetaxel/carboplatin/trastuzumab] 306 (59%), anthracycline and taxane regimens-85 (16%), single-agent taxane 48 (9%), other regimens or T without chemotherapy-79 (15%). The database lock out date was May 31st 2015. The median follow-up (FU) time is 50.6 (1.4-156.6) months. The overall relapse rate (RR) in the whole population is 8.9% (AdjT 9.4%/NAdjT 7.6%) and distant RR is 8.3% (AdjT 9.1%/NAdjT 6.2%). OS rate in the whole study population is 93.4% (AdjT 92.5%/NAdjT 95.9%). RR was lower in pts with HR+ [7.2% (AdjT 7.1%/NAdjT 7.8%)] than in those with HR- [10.6% (AdjT 11.9%/NAdjT 7.4%)] disease. Among all the subgroups the lowest RR was observed in the HR+/LN- subgroup (2.7%) whilst the highest was in the HR-/LN+ subgroup (15.5%). Pts treated in the NAdjT cohort had a pathological complete response (pCR) rate of 38.6%. In the whole study population the median time to relapse (TTR) was 31.8 (7.9-97.6) months with no difference between AdjT and NAdjT cohorts. 87% of all relapses happened within 60 months of first T. Out of 6 delayed relapses (after month 60) 4 were HR+, 1was HR unknown and 1 was HR- in the form of a contralateral axillary recurrence, possibly from a second occult breast primary. Among pts treated prior to March 2010 (N=267), who have a minimum FU of 5 yrs, the RFS is 86.5% and the OS rate of 89.1%. Conclusions. The prognosis of pts with HER2+ ESBC in the T era is excellent. Despite the large proportion of pts with LN+ disease in our database, over 90% are alive at almost 5 years. HR+ confers a better prognosis than HR- in both LN+ and LN- disease. Long-term outcome data show that nearly 90% of all relapses occur within 5 yrs from initiation of anti-HER2 therapy especially in the HR- subgroup. Late relapse is rare in HR- pts. Adjuvant hormonal therapy is likely to contribute meaningfully to the favourable outcome of HR+/HER2+ ESBC and may explain the discordance between the improved survival of ER+ Adj pts and the improved pCR reported for neoAdj T in ER+ pts. Citation Format: Bose R, Zanoni D, Gullo G, Fennelly D, Walshe J, Ballot J, Defrein A, O'Donovan N, Mc Dermott E, Evoy D, Silva N, Crown J. Long term follow up of patients (pts) with HER2positive (H+) early stage breast cancer (ESBC) treated with trastuzumab (T). [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 P4-12-01.

Background Young women ( Methods YWBC were identified from pathology databases at 2 tertiary centers. Pts were divided into 2 cohorts: BC diagnoses from 2000-2007 (G1) and 2008-2015 (G2). ClinPath and Rx data were retrieved from clinical, radiology and histology databases. Statistical analysis was performed using SPSS. Results We identified 347 pts. Tumor features are shown in Table I. Median age is 36 (23-39). By histology, 90.8% (n=315) had invasive ductal carcinoma, 53.1% (n=181) had Grade III BC and 56.3% (n=171) had lymphovascular invasion. Pregnancy-associated BC occurred in 10.7% (n=34). Mastectomy (MX) was performed in 53% (n=176) and axillary lymph node clearance (ALNC) in 63.8% (n=192 [G1: 84.3% vs. G2: 48.6%, p Table 1Tumor features Group 1 (n=149)Group 2 (n=198)Total (n=347)p-valueMedian tumor size (mm) 252222.5p=0.115Node positivity 88 (60.3%)100(51.5%)188 (55.3%)p=0.109Median node count 4 (1-44)1 (1-30)2 (1-44)p Rx characteristics are shown in Table 2. 85 pts received neo-adjuvant therapy (NAT); 48.3% (n=41) ER+/HER2-, 27% (n=23) HER2+ and 24.7% (n=21) TNBC. Pts receiving NAT in G2 trended towards improved pCR rate (G2: 24.6% vs G1: 8.3%, p=0.057). Endocrine Rx alone was received by 9.8% (n=22); 13.6% (n=18) in G2 vs 4.3% (n=4) in G1. OncotypeDx(ODx) was used in 23 pts (14.9%) (median score 17), 1 had a DR (ODx Score = 18). Table 2Tx characteristics n=347 Chemotherapy Total300(86.4%) NAT85 (28.3%)Pathological Complete Response (pCR)* pCR (n=16, 19.8%)No pCR (n=65, 80.2%) ER+/HER2-18.8%(n=3)53.9% (n=35) HER2+/ER+18.8%(n=3)13.8% (n=9) HER2+/ER-31.2% (n=5)9.2% (n=6) TNBC31.2%(n=5)23.1%(n=15)Local relapse 1 (6.2%)1(1.5%)Distant relapse (DR) 022(33.8%)*Data incomplete n=4 DR occurred in 50 pts (16%), including 13 (20.3%) HER2+ pts. Of note, 92.3% (n=12) of these were in G1. Relapse rates (RR) in TN and ER+/HER- pts were 19.6% (n=11) and 13.7% (n=26) respectively. There was a higher RR in G1 (34.8% vs 11.4%, p Conclusion In line with existing data, locally advanced dx is more prevalent in YWBC. MX and ALNC rates were high and most received multimodal Rx. The extent of axillary surgery declined. Pts in G2 had lower volume BC at diagnosis suggesting increasing awareness. TN and HER2+ subtypes accounted for a slightly higher proportion of BC cases. Pts with PCR had better outcomes. Only 16% relapsed with metastatic dx. The impact of HER2 Rx is highlighted by reduced RR in HER2+ G2 pts. Outcomes were unchanged in pts with ER+/HER2- and TNBC. These remain a priority for future research. Citation Format: Greally M, Kielty J, Das G, Malouf C, O'Riordan L, Coleman N, Quinn C, McDermott E, Gullo G, Kelly C, Crown J, Prichard R, Walshe J. Retrospective cohort study of patients (pts) diagnosed with breast cancer (BC)