Multimodal, Technology-Assisted Intervention for the Management of Menopause after Cancer Improves Cancer-Related Quality of Life-Results from the Menopause after Cancer (Mac) Study.

BACKGROUND: Vasomotor symptoms (VMSs) associated with menopause represent a significant challenge for many patients after cancer treatment, particularly if conventional menopausal hormone therapy (MHT) is contraindicated. METHODS: The Menopause after Cancer (MAC) Study (NCT04766229) was a single-arm phase II trial examining the impact of a composite intervention consisting of (1) the use of non-hormonal pharmacotherapy to manage VMS, (2) digital cognitive behavioral therapy for insomnia (dCBT-I) using Sleepio (Big Health), (3) self-management strategies for VMS delivered via the myPatientSpace mobile application and (4) nomination of an additional support person/partner on quality of life (QoL) in women with moderate-to-severe VMS after cancer. The primary outcome was a change in cancer-specific global QoL assessed by the EORTC QLC C-30 v3 at 6 months. Secondary outcomes included the frequency of VMS, the bother/interference of VMS and insomnia symptoms. RESULTS: In total, 204 women (82% previous breast cancer) with a median age of 49 years (range 28-66) were recruited. A total of 120 women completed the protocol. Global QoL scores increased from 62.2 (95%CI 58.6-65.4) to 70.4 (95%CI 67.1-73.8) at 6 months (p < 0.001) in the intention to treatment (ITT) cohort (n = 204) and from 62 (95%CI 58.6-65.4) to 70.4 (95%CI 67.1-73.8) at 6 months (p < 0.001) in the per-protocol (PP) cohort (n = 120). At least 50% reductions were noticed in the frequency of VMS as well as the degree of bother/interference of VMS at six months. The prevalence of insomnia reduced from 93.1% at the baseline to 45.2% at 6 months (p < 0.001). The Sleep Condition Indicator increased from 8.5 (SEM 0.4) to 17.3 (SEM 0.5) (p < 0.0005) in the ITT cohort and 7.9 (SEM 0.4) to 17.3 (SEM 0.5) (p < 0.001) in the PP cohort. CONCLUSIONS: A targeted composite intervention improves the quality of life for cancer patients with frequent and bothersome vasomotor symptoms with additional benefits on frequency, the bother/interference of VMS and insomnia symptoms.

Real-World Analysis of the Clinical and Economic Impact of the 21-Gene Recurrence Score (RS) in Invasive Lobular Early-Stage Breast Carcinoma in Ireland.

Background: This study, using real-world data, assesses the impact of RS testing on treatment pathways and the associated economic consequences of such testing. This paper pertains to lobular breast cancer. Methods: A retrospective, observational study was undertaken between 2011 and 2019 on a cross-section of hormone receptor-positive (HR+), HER2-negative, lymph node-negative, early-stage breast cancer patients. All patients had ILC and had RS testing in Ireland. The patient population is representative of the national population. Patients were classified as low (RS ≤ 25) or high (RS > 25) risk. Patients aged ≤50 were stratified as low (RS 0-15), intermediate (RS 16-25), or high risk (RS > 25). Results: A total of 168 patients were included, most of whom had grade 2 (G2) tumors (n = 154, 92%). Overall, 155 patients (92.3%) had low RS (≤25), 12 (7.1%) had high RS (>25), and 1 (0.6%) had unknown RS status. In 29 (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%). Post RS testing, 126 patients (78%) had a change in chemotherapy recommendation; all to hormone therapy. In total, only 35 patients (22%) received chemotherapy. RS testing achieved a 75% reduction in chemotherapy use, resulting in savings of €921,543.84 in treatment costs, and net savings of €387,283.84. Conclusions: The use of this test resulted in a 75% reduction in chemotherapy and a significant cost savings in our publicly funded health system.

Breast Cancer Index and Prediction of Extended Aromatase Inhibitor Therapy Benefit in Hormone Receptor-Positive Breast Cancer from the NRG Oncology/NSABP B-42 Trial.

PURPOSE: BCI (H/I) has been shown to predict extended endocrine therapy (EET) benefit. We examined BCI (H/I) for EET benefit prediction in NSABP B-42, which evaluated extended letrozole therapy (ELT) in patients with hormone receptor-positive breast cancer after 5 years of ET. EXPERIMENTAL DESIGN: A stratified Cox model was used to analyze RFI as the primary endpoint, with DR, BCFI, and DFS as secondary endpoints. Because of a nonproportional effect of ELT on DR, time-dependent analyses were performed. RESULTS: The translational cohort included 2,178 patients (45% BCI (H/I)-High, 55% BCI (H/I)-Low). ELT showed an absolute 10-year RFI benefit of 1.6% (P = 0.10), resulting in an underpowered primary analysis (50% power). ELT benefit and BCI (H/I) did not show a significant interaction for RFI (BCI (H/I)-Low: 10 years absolute benefit 1.1% [HR, 0.70; 95% confidence interval (CI), 0.43-1.12; P = 0.13]; BCI (H/I)-High: 2.4% [HR, 0.83; 95% CI, 0.55-1.26; P = 0.38]; Pinteraction = 0.56). Time-dependent DR analysis showed that after 4 years, BCI (H/I)-High patients had significant ELT benefit (HR = 0.29; 95% CI, 0.12-0.69; P < 0.01), whereas BCI (H/I)-Low patients were less likely to benefit (HR, 0.68; 95% CI, 0.33-1.39; P = 0.29; Pinteraction = 0.14). Prediction of ELT benefit by BCI (H/I) was more apparent in the HER2- subset after 4 years (ELT-by-BCI (H/I) Pinteraction = 0.04). CONCLUSIONS: BCI (H/I)-High versus BCI (H/I)-Low did not show a statistically significant difference in ELT benefit for the primary endpoint (RFI). However, in time-dependent DR analysis, BCI (H/I)-High patients experienced statistically significant benefit from ELT after 4 years, whereas (H/I)-Low patients did not. Because BCI (H/I) has been validated as a predictive marker of EET benefit in other trials, additional follow-up may enable further characterization of BCI's predictive ability.

Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.PALOMA-2 demonstrated statistically and clinically significant improvement in progression-free survival with palbociclib plus letrozole versus placebo plus letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (ABC). Here, we report results for the secondary end point overall survival (OS). Postmenopausal women (N = 666) with ER+/HER2- ABC without previous systemic therapy for ABC were randomly assigned 2:1 to palbociclib plus letrozole or placebo plus letrozole. After a median follow-up of 90.1 months, 405 deaths were observed and 155 patients were known to be alive. The median OS was 53.9 months (95% CI, 49.8 to 60.8) with palbociclib plus letrozole versus 51.2 months (95% CI, 43.7 to 58.9) with placebo plus letrozole (hazard ratio [HR], 0.96 [95% CI, 0.78 to 1.18]; stratified one-sided P = .34). An imbalance in the number of patients with unknown survival outcome between the treatment arms (13.3% v 21.2%, respectively) limited interpretation of OS results. With recovered survival data, the median OS was 53.8 (95% CI, 49.8 to 59.2) versus 49.8 months (95% CI, 42.3 to 56.4), respectively (HR, 0.92 [95% CI, 0.76 to 1.12]; one-sided P = .21). OS was not significantly improved with palbociclib plus letrozole compared with placebo plus letrozole.

Pilot study of the implementation of G8 screening tool, Cognitive screening assessment and Chemotherapy Toxicity assessment in older adults with cancer in a Tertiary University Hospital in Ireland.

BACKGROUND: Comprehensive geriatric assessment (CGA) is recommended by international guidelines prior to initiation of systemic anti-cancer treatment (SACT). In practice, CGA is limited by time constraints, lack of resources and expert interpretation. AIMS: The primary objective of this pilot study was to establish the prevalence of frailty (assessed by G8), cognitive impairment (assessed by Mini-Cog), and risk of chemotherapy toxicity (assessed by CARG Chemo-Toxicity Calculator) among patients (pts) ≥65 years commencing SACT. We selected these three screening tools due to the ease of conducting them in a busy outpatient setting. In addition, they have been validated to predict frailty and risk of toxicity from SACT among older adults with cancer. METHODS: Eligible participants were identified from medical oncology clinics. Assessments were conducted in an outpatient setting by treating physicians. Pt records were reviewed to gather demographic and cancer details. Statistical analyses were conducted using SPSS statistical software. RESULTS: Sixty-three participants were enrolled. The mean age of participants was 73yrs (range=65-88). Thirty-three (52.4%) were female and 30 (47.6%) were male. The majority (n=38, 60.3%) had metastatic cancer. The mean G8 score was 11.9 (range=6-19). Eighty-three percent had a G8 score ≤14. Mini-Cog was positive in 13 pts (21%). The mean CARG score was 7.5 (range=0-16), and 80% had a risk of at least 50% grade ≥3 toxicity. Of these, 48 (76.2%) received chemotherapy and 15 (23.8%) received non-cytotoxic SACT. In multi-variate analyses, age, cancer type, treatment type, and disease stage did not impact G8, Mini-Cog, or CARG scores. CONCLUSIONS: Our study has several limitations but suggests that the majority of older adults with cancer would qualify for formal CGA assessment. The risk of high-grade toxicity from SACT is substantial in this cohort. Chronological age was not found to negatively impact pts' frailty, cognition, or risk of toxicity.

The effects of adding palbociclib to endocrine therapy to treat advanced breast cancer: a plain language summary of a study using the PALOMA-2 and PALOMA-3 trial results.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article that reported results of a study using data from two phase 3 clinical trials called "PALOMA-2" and "PALOMA-3." Both PALOMA-2 and PALOMA-3 trials included women with HR+/HER2- advanced breast cancer. HR+/HER2- breast cancer means the breast cancer cells of these women have receptors for female sex hormones and little or no HER2 receptors. Both PALOMA trials tested the effect of adding a medication called palbociclib (brand name, Ibrance®) to a hormone therapy. Hormone therapy, also known as endocrine therapy, is a treatment that blocks or removes hormones that cause cancer cells to grow and divide. In both trials, women took endocrine therapy with either palbociclib or a placebo. WHAT WAS THE AIM OF THIS STUDY?: The researchers aimed to see if the results from the PALOMA trials were similar for subgroups of women in the 2 trials. The subgroups in the study included women who shared certain features about their cancer or treatment history, for example, women whose cancer had spread to the liver. For each subgroup, the study compared the results from the 2 treatment groups: (1) women who took palbociclib plus endocrine therapy, and (2) women who took placebo plus endocrine therapy. WHAT WERE THE RESULTS & WHAT DO THEY MEAN?: The same effect was found in all subgroups. Compared with those who took placebo, women who took palbociclib lived longer without their cancer getting worse (growing or spreading). Also, among women who had chemotherapy after stopping the trial treatment, those who took palbociclib started chemotherapy later than those who took placebo. Because palbociclib slows cancer growth and leads to tumor shrinkage, this may have played a part in starting chemotherapy later. These results show that palbociclib plus endocrine therapy is better at slowing the progression of advanced HR+/HER2- breast cancer than endocrine therapy alone. This can be said for women with different advanced HR+/HER2- breast cancer features and treatment history. Overall, the results support women taking palbociclib with an endocrine therapy if they have advanced HR+/HER2- breast cancer.

Predictive modelling of response to neoadjuvant therapy in HER2+ breast cancer.

HER2-positive (HER2+) breast cancer accounts for 20-25% of all breast cancers. Predictive biomarkers of neoadjuvant therapy response are needed to better identify patients with early stage disease who may benefit from tailored treatments in the adjuvant setting. As part of the TCHL phase-II clinical trial (ICORG10-05/NCT01485926) whole exome DNA sequencing was carried out on normal-tumour pairs collected from 22 patients. Here we report predictive modelling of neoadjuvant therapy response using clinicopathological and genomic features of pre-treatment tumour biopsies identified age, estrogen receptor (ER) status and level of immune cell infiltration may together be important for predicting response. Clonal evolution analysis of longitudinally collected tumour samples show subclonal diversity and dynamics are evident with potential therapy resistant subclones detected. The sources of greater pre-treatment immunogenicity associated with a pathological complete response is largely unexplored in HER2+ tumours. However, here we point to the possibility of APOBEC associated mutagenesis, specifically in the ER-neg/HER2+ subtype as a potential mediator of this immunogenic phenotype.

Ten-year update: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-42 randomized trial: extended letrozole therapy in early-stage breast cancer.

BACKGROUND: The National Surgical Adjuvant Breast and Bowel Project B-42 trial evaluated extended letrozole therapy (ELT) in postmenopausal breast cancer patients who were disease free after 5 years of aromatase inhibitor (AI)-based therapy. Seven-year results demonstrated a nonstatistically significant trend in disease-free survival (DFS) in favor of ELT. We present 10-year outcome results. METHODS: In this double-blind, phase III 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 randomly assigned to 5 years of letrozole or placebo. Primary endpoint was DFS, defined as time from random assignment to breast cancer recurrence, second primary malignancy, or death. All statistical tests are 2-sided. RESULTS: Between September 2006 and January 2010, 3966 patients were randomly assigned (letrozole: 1983; placebo: 1983). Median follow-up time for 3923 patients included in efficacy analyses was 10.3 years. There was statistically significant improvement in DFS in favor of letrozole compared with placebo (hazard ratio [HR] = 0.85, 95% confidence interval [CI] = 0.74 to 0.96; P = .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 (HR = 0.97, 95% CI = 0.82 to 1.15; P = .74). Letrozole statistically significantly reduced breast cancer-free interval events (HR = 0.75, 95% CI = 0.62 to 0.91; P = .003; absolute difference in cumulative incidence = 2.7%) and distant recurrences (HR = 0.72, 95% CI = 0.55 to 0.92; P = .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 improved breast cancer-free interval and distant recurrences without improving overall survival. Careful assessment of potential risks and benefits is necessary for selecting appropriate candidates for ELT.

Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer.

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.).

Using menopausal hormone therapy after a cancer diagnosis in Ireland.

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.

Effect of palbociclib plus endocrine therapy on time to chemotherapy across subgroups of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer: Post hoc analyses from PALOMA-2 and PALOMA-3.

BACKGROUND: Previous analyses from the PALOMA-2 and PALOMA-3 studies showed that palbociclib (PAL) plus endocrine therapy (ET) prolongs time to first subsequent chemotherapy (TTC) versus placebo (PBO) plus ET in the overall population of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative (HR+/HER2-) advanced breast cancer (ABC). Here, we evaluated TTC in relevant patient subgroups. METHODS: These post hoc analyses evaluated TTC by subgroup using data from 2 randomized, phase 3 studies of women with HR+/HER2- ABC. In PALOMA-2, postmenopausal patients previously untreated for ABC were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus letrozole (LET; 2.5 mg/day; n = 444) or PBO plus LET (n = 222). In PALOMA-3, premenopausal or postmenopausal patients whose disease had progressed after prior ET were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus fulvestrant (FUL; 500 mg; n = 347) or PBO plus FUL (n = 174). RESULTS: First subsequent chemotherapy was received by 35.5% and 56.2% in PALOMA-2 and PALOMA-3 after progression on palbociclib plus ET or placebo plus ET. Across all subgroups analyzed, the median progression-free survival (PFS) was longer in the PAL plus ET arm than the PBO plus ET arm. TTC was longer with PAL plus ET versus PBO plus ET across the same patient subgroups in both studies. CONCLUSIONS: Across all subgroups, PAL plus ET versus PBO plus ET had longer median PFS and resulted in prolonged TTC in both the PALOMA-2 and PALOMA-3 studies. Pfizer Inc (NCT01740427, NCT01942135).

Hepatic resection for breast cancer related liver metastases: A single institution experience.

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 < 0.01) and worse overall survival (p = 0.02). 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.

The menopause after cancer study (MACS) - A multimodal technology assisted intervention for the management of menopausal symptoms after cancer - Trial protocol of a phase II study.

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 NCT04766229.

Who are the women who enrolled in the POSITIVE trial: A global study to support young hormone receptor positive breast cancer survivors desiring pregnancy.

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 <35 years at enrolment (42.7 %), had mastectomy (59.0 %) and received tamoxifen alone (59.8 %). More Asian women were nulliparous (81.0 %), had node-negative disease (76.2%) and received tamoxifen + OFS (56.0 %). More European women had received chemotherapy (69.3 %). INTERPRETATION: The characteristics of participants in the POSITIVE study provide insights to which patients and doctors considered it acceptable to interrupt ET to pursue pregnancy. Similarities and variations from a regional, sociodemographic, disease and treatment standpoint suggest specific sociocultural attitudes across the world.

Efficacy and safety of palbociclib in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with preexisting conditions: A post hoc analysis of PALOMA-2.

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).

Pregnancy-associated breast cancer: evaluating maternal and foetal outcomes. A national study.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Phase Ib Trial of Copanlisib, A Phosphoinositide-3 Kinase (PI3K) Inhibitor, with Trastuzumab in Advanced Pre-Treated HER2-Positive Breast Cancer "PantHER".

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.

Systemic therapy for metastatic HER2-positive breast cancer.

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.

Progression-free Survival Outcome Is Independent of Objective Response in Patients With Estrogen Receptor-positive, Human Epidermal Growth Factor Receptor 2-negative Advanced Breast Cancer Treated With Palbociclib Plus Letrozole Compared With Letrozole: Analysis From PALOMA-2.

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.

Where youth matters-clinicopathologic characteristics and emerging trends in treatment and outcomes in young Irish women with breast cancer.

BACKGROUND: 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. METHODS: 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). RESULTS: 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 < 0.001]). One hundred-seventy patients (49%) were ER + HER2-, 88 (25.5%) were HER2+, and 58 (16.8%) were triple negative. Eighty patients (23.2%) received neoadjuvant therapy. Pathological complete response rates were statistically similar between C1 and C2 [C1 1 (0.9%) vs C2 16 (6.8%) p = 0.1]. Distant relapse occurred in 59 (19%) patients. There was a higher relapse rate (RR) in C1 [27 (32.1%) vs. 32 (15.7%), p < 0.002). HER2+ and ER+ HER2- patients in C1 had higher RRs than C2. Median overall survival in patients with metastatic disease was 29 months (range 2-119 months). CONCLUSION: Locally advanced disease was more prevalent in YWBC. Mastectomy and ALNC rates were high and most received multimodal treatment. The extent of axillary surgery declined over time. Outcomes were unchanged in triple negative patients. These remain a priority for research.