mBC Treatment Research Articles

Analysis of the Clinical Advancements for BRCA-Related Malignancies Highlights the Lack of Treatment Evidence for BRCA-Positive Male Breast Cancer.

Simple SummaryMale breast cancer (MBC) is an orphan disease that is on the rise but remains understudied. Mutations in genes sensitive to DNA damage response, BRCA1 and BRCA2, are strongly implicated in MBC development. Evidence-based guidance for the treatment of MBC that have BRCA mutations is lacking with most published data arising from retrospective or case studies with small patient cohorts. Here, we review the lack of treatment evidence for BRCA-related MBC. We also highlight the impact of poly(ADP-ribose) polymerase (PARP) inhibitors which are used in the clinical management of BRCA-related female breast cancer and prostate cancer. In turn, we demonstrate the requirement for national and global collaborative efforts to address the striking unmet need for dedicated BRCA-related MBC research, including studies to better understand disease trajectory and improve clinical outcomes.Male breast cancer (MBC) is a rare disease that accounts for less than 1% of all breast cancers and male malignancies. Despite recognised clinico-pathological and molecular differences to female breast cancer (FBC), the clinical management of MBC follows established FBC treatment strategies. Loss of function mutations in the DNA damage response genes BRCA1 and BRCA2, have been strongly implicated in the pathogenesis of MBC. While there have been extensive clinical advancements in other BRCA-related malignancies, including FBC, improvements in MBC remain stagnant. Here we present a review that highlights the lack of treatment evidence for BRCA-related MBC and the required national and global collaborative effort to address this unmet need. In doing so, we summarise the transformative clinical advancements with poly(ADP-ribose) polymerase (PARP) inhibitors in other BRCA-related cancers namely, FBC and prostate cancer.

KEYNOTE-B49: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy in patients with HR+/HER2- locally recurrent inoperable or metastatic breast cancer.

TPS1118 Background: HR+/HER2− advanced breast cancer that progresses on endocrine therapy is treated with chemotherapy (chemo). The phase 1b KEYNOTE-028 trial showed durable activity with pembrolizumab (pembro) monotherapy in previously treated HR+/HER2−, PD-L1–positive (combined positive score [CPS] ≥1) advanced breast cancer. KEYNOTE-B49 (NCT04895358) is a phase 3, randomized, double-blind study of pembro + chemo vs placebo (pbo) + chemo in centrally assessed PD-L1–positive, HR+/HER2− locally recurrent inoperable or metastatic breast cancer (mBC) after progression on prior endocrine therapy. Methods: ∼800 patients (pts) with HR+/HER2− locally recurrent inoperable or mBC who are candidates for chemo (no prior chemo for metastatic disease) with PD-L1 CPS ≥1 and documented progression on prior endocrine therapy will be enrolled. Prior endocrine therapy comprises ≥2 lines (≥1 in combination with a CDK4/6 inhibitor) in the metastatic setting or 1 line with CDK4/6 inhibitor treatment for mBC in pts who had a relapse within 24 mo of primary surgery. Pts without prior CDK4/6 inhibitor treatment may enroll if they had progressed within 6 mo of starting endocrine therapy for metastatic disease and had previously relapsed within 24 mo of primary tumor surgery while on adjuvant endocrine therapy. Pts are randomized 1:1 to receive pembro 200 mg IV or pbo Q3W, each in combination with investigator’s choice of chemo: paclitaxel 90 mg/m2 IV on days 1, 8, and 15 Q4W; nab-paclitaxel 100 mg/m2 IV on days 1, 8, and 15 Q4W; liposomal doxorubicin 50 mg/m2 IV on day 1 Q4W; or capecitabine 1000 mg/m2 PO BID on days 1–14 Q3W. Randomization is stratified by tumor PD-L1 (CPS 1–9 vs ≥10), presence of visceral metastases (yes vs no), and chemo on-study (taxanes vs liposomal doxorubicin vs capecitabine). Treatment is continued until disease progression, unacceptable toxicity, withdrawal, or, for pembro/pbo, completion of 35 cycles (̃2 years); chemo can be continued per investigator discretion. Tumor PD-L1 status is determined centrally using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies; Carpinteria, CA, USA). Radiologic assessments are performed Q9W for 54 wk and then Q12W thereafter. AEs occurring from randomization until 30 d after treatment discontinuation (90 d for serious AEs) are graded per NCI-CTCAE v 5.0. Primary endpoints are PFS per RECIST v1.1 by BICR and OS in pts with PD-L1 CPS ≥10 and ≥1 tumors, separately. Enrollment is ongoing at 204 international sites. Clinical trial information: NCT04895358.

Treatment patterns and medical costs of metastatic breast cancer care in the United States.

e18834 Background: Substantial advances in treatment of metastatic breast cancer (mBC) have led to changes in clinical practice and treatment costs in the United States in the past decade. We aimed to identify treatment patterns in mBC patients by subgroup and year after mBC diagnosis and associated costs from payer and societal perspectives. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database (1/2011-5/2021). We excluded cases that were male, had < 6 months of follow up, no treatment data, no structured data within 90 days of diagnosis, participated in clinical trials, had non-breast invasive cancers, received therapies not used in mBC, had no data on human epidermal growth factor (HER2) and hormone receptor (HR) status. We classified patients into four subgroups: HER2-HR+, HER2+HR+, HER2+HR-, and Triple Negative (TNBC). We calculated anti-cancer and supportive drug costs at the patient level and mean costs by year after diagnosis for each subgroup. We used average wholesale prices (AWP, from McKesson Corporation) for payer perspective and Medicare prices (part B payment limit data, Part D Drug Spending Dashboard) for societal perspective. We estimated costs up to year 5 after diagnosis of mBC (< 8% received treatment after year 5). Results: 15,215 patients met the criteria (64.41% non-Hispanic White, 66.85% HER2-HR+, 18.30% HER2+HR+, 5.27% HER2+HR-, 9.58% TNBC). AWP and Medicare cost estimates by year after diagnosis and subgroup are shown in Table. 334,812 for HER2+HR+, $284,609 for HER2+HR-, $104,774 for HER2-HR+, and $54,355 for the TNBC. We observed an increase in annual costs between years 2011-2021 in most subgroups. This increase was most substantial for HER2-HR+ patients. From 2011 to 2019 (most recent complete year 1 data is for patients diagnosed in 2019), annual Medicare treatment costs in year 1 increased from $12,986 to $80,563 for HER2-HR+, $99,997 to $156,712 for HER2+HR+, and $31,397 to $53,775 for TNBC. There was no increase in costs of treating HER2+HR- in year 1, but an increase in year 2 (from $90,427 to $129,690 between 2011-2019). Conclusions: mBC treatment costs vary significantly by receptor subtype and years after diagnosis. Annual costs increased over time. Costs were greatest for HER2+ and lowest for TNBC.[Table: see text]

MO348: Methylene Blue Beneficial Effect in Treatment of Renal Calculi in Patient With Recurrent Urinary Tract Infection

Abstract BACKGROUND AND AIMS Assessment of efficacy of fixed combination of cranberry and sage extract with methylene blue (MBC) in dose of 30 mg twice daily in the prevention and management of chronic renal calculous disease. METHOD In 87 patients who complained recurrent urinary tract infection (UTI)—55 pts with pyelonephritis and 32 with cystitis—at least three episodes in 12 months, the impact of 3 months treatment of MBC with on renal calculi was investigated. All patients were older than 18 years without any biochemical or congenital kidney abnormalities, coagulopathies with size of renal stone over 10 mm. Simultaneous administration of phenothiazine derivatives, SSRI, MAO, tricyclic or any other antidepressants we excluded. A total of 39 (45%) of the patients with a history of nephrolithotomy in the past were included. RESULTS In most cases, patients were supervised during 12 months with 2–3 courses of MBC during the year. A total of 18 pts (21%) have passed no further stones with dramatic improvement of quality of life, and 47 (54%) have improved clinically with reduction of calculi size. A total of 79 pts (91%) reported overall clinical improvement of UTI symptoms and quality of life. The main disadvantage during MBC administration could be discoloration of the urine in light blue or green color. No side or adverse effects were observed during the whole period of the trial. CONCLUSION Methylene blue could be a promising solution in the management of patients with multiple small renal calculi, especially with necessity to reduce the level of concomitant infection without antibiotic and may be useful in the prevention of new stone formation.

Evaluation of Information Theoretic Network Meta-analysis to Rank First-Line Anticancer Regimens for Hormone Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer

Hormone receptor-positive, ERBB2 (formerly HER2/neu)-negative metastatic breast cancer (HR-positive, ERBB2-negative MBC) is treated with targeted therapy, endocrine therapy, chemotherapy, or combinations of these modalities; however, evaluating the increasing number of treatment options is challenging because few regimens have been directly compared in randomized clinical trials (RCTs), and evidence has evolved over decades. Information theoretic network meta-analysis (IT-NMA) is a graph theory-based approach for regimen ranking that takes effect sizes and temporality of evidence into account. To examine the performance of an IT-NMA approach to rank HR-positive, ERBB2-negative MBC treatment regimens. HemOnc.org, a freely available medical online resource of interventions, regimens, and general information relevant to the fields of hematology and oncology, was used to identify relevant RCTs. All primary and subsequent reports of RCTs of first-line systemic treatments for HR-positive, ERBB2-negative MBC that were referenced on HemOnc.org and published between 1974 and 2019 were included. Additional RCTs that were evaluated by a prior traditional network meta-analysis on HR-positive, ERBB2-negative MBC were also included. RCTs were independently extracted from HemOnc.org and a traditional NMA by separate observers. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for NMA with several exceptions: the risk of bias within individual studies and inconsistency in the treatment network were not assessed. Regimen rankings generated by IT-NMA based on clinical trial variables, including primary end point, enrollment number per trial arm, P value, effect size, years of enrollment, and year of publication. A total of 203 RCTs with 63 629 patients encompassing 252 distinct regimens were compared by IT-NMA, which resulted in 151 rankings as of 2019. Combinations of targeted and endocrine therapy were highly ranked, especially the combination of endocrine therapy with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. For example, letrozole plus palbociclib was ranked first and letrozole plus ribociclib, third. Older monotherapies that continue to be used in RCTs in comparator groups, such as anastrozole (251 of 252) and letrozole (252), fell to the bottom of the rankings. Many regimens gravitated toward indeterminacy by 2019. In this network meta-analysis study, combination therapies appeared to be associated with better outcomes than monotherapies in the treatment of HR-positive, ERBB2-negative MBC. These findings suggest that IT-NMA is a promising method for longitudinal ranking of anticancer regimens from RCTs with different end points, sparse interconnectivity, and decades-long timeframes.

Real-world clinical outcomes of patients with BRCA-mutated, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer: a CancerLinQ\xae study

PurposeTo investigate real-world clinical outcomes in patients with BRCA-mutated (BRCAm), HER2-negative metastatic breast cancer (mBC) according to BRCA and hormone receptor (HR) status.MethodsPatients diagnosed with HER2-negative mBC between 01 January 2010 and 31 December 2018 were retrospectively identified from the American Society of Clinical Oncology’s CancerLinQ Discovery® database. Time to first subsequent therapy or death (TFST) from date of mBC diagnosis and start of first-line treatment for mBC and overall survival (OS) from date of mBC diagnosis were investigated according to BRCA status (BRCAm, BRCA wild type [BRCAwt] or unknown BRCA [BRCAu]) and HR status (positive/triple negative breast cancer [TNBC]). Follow-up continued until 31 August 2019 (i.e. minimum of 8 months).Results3744 patients with HER2-negative mBC were identified (BRCAwt, n = 460; BRCAm, n = 83; BRCAu, n = 3201) (HR-positive, n = 2738). Median (Q1, Q3) age was 63.0 (54.0, 73.0) years. Median (95% confidence interval [CI]) TFST (months) from mBC diagnosis was as follows: HR-positive, 7.7 (5.0, 11.2), 8.3 (6.6, 10.2) and 9.4 (8.7, 10.1); TNBC, 5.4 (3.9, 12.4), 5.6 (4.7, 6.6) and 5.4 (5.0, 6.2) for BRCAm, BRCAwt and BRCAu, respectively. Median (95% CI) OS (months) was as follows: HR-positive, 41.1 (31.5, not calculable), 55.1 (43.5, 65.5) and 33.0 (31.3, 34.8); TNBC, 13.7 (11.1, not calculable), 14.4 (10.7, 17.0) and 11.7 (10.3, 12.8) for BRCAm, BRCAwt and BRCAu, respectively.ConclusionWhen stratified by HR status, TFST and OS were broadly similar for patients with HER2-negative mBC, irrespective of BRCA status. Further global real-world studies are needed to study outcomes of this patient population.

Abstract P3-12-27: Characteristics and survival outcomes of male breast cancer in Sao Paulo state of Brazil: A population-based study

Abstract IntroductionMale breast cancer (MBC) is uncommon tumor that represents only 0,5% of all tumor diagnoses in men. In general, the age of incidence of MBC is, on average, 5-10 years later than women and have more advanced stage at diagnosis and worse prognosis. International recommendations for staging and treatment for MBC are the same as female breast cancer. Due to the rarity of the tumor, few data are available related to MBC. The aim of this study was to evaluate the clinicopathological characteristics, treatment trends and survival outcomes in MBC in Sao Paulo State of Brazil.MethodsThis population-based study had included men diagnosed with invasive breast cancer between January 2000 and June 2020 from Fundação Oncocentro de Sao Paulo. Patients were described according to age, education level, treatment modalities and medical practice. Categorical variables are described as percentages and frequencies. The association between demographic and treatment factors and overall survival was evaluated using a Cox Proportional Hazard (PH) regression model while accounting for different lengths of participant follow-up. Uni- and multivariable Cox proportional-hazards model were used to estimate hazard ratios with corresponding 95% confidence intervals for OS. The Kaplan-Meier (KM) curves were used to visually display survival curves, and the log-rank test were used to compare the estimated KM curves. ResultsA total of 907 MBC patients were included (825 patients had invasive ductal carcinoma; 64, had invasive lobular carcinoma;18, had especial subtypes). The age at diagnosis were <45y, 51-70y, >70y in 12.2%, 51.5% and 27.1% of patients, respectively. The proportion of stage I, II, III and IV were 19.5%, 36.6%, 31,5% and 12.3%, respectively (Table 1). OS by stage at diagnosis was presented in the Figure 1. For each stage I, II, III and IV, 5- and 10-years OS were, respectively, 87.9% and 77.8%, 79.9% and 58.9%, 51.6% and 24.5%, 20.0% and 5.6%. In the multivariable analyses adjusted for practice (public or private), education (low or medium/high), age, stage at diagnosis and treatment. modalities, the significant independent predictor for OS was stage at diagnosis only Figure 2. ConclusionMBC tends to be diagnosed at a more advanced stage and older age at the time of diagnosis. Type of practice, age, treatment modalities and educational level did not influence survival outcomes. Stage at diagnosis was the most important factor related to the OS. Citation Format: Ridânia de Oliveira Frederice, Allan AndressonLima Pereira, Felipe EduardoMartins de Andrade, Samir Abdallah Hanna, Heloisa de Andrade Carvalho, Gustavo Nader Marta. Characteristics and survival outcomes of male breast cancer in Sao Paulo state of Brazil: A population-based 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 P3-12-27.

Abstract P2-13-16: Dual HER2-blockade with pertuzumab (P) and trastuzumab (T) in patients with HER2-positive metastatic breast cancer (mBC) relapsing after adjuvant treatment with T. Results from a German non-interventional study (NIS) HELENA (NCT01777958)

Abstract Background: Treatment of HER2 overexpressing mBC with the HER2 directed antibody combination of P and T became standard of care since marketing authorization of P based on the results of the randomized controlled CLEOPATRA trial (NCT 00567190). NIS HELENA was designed to document effectiveness and safety in clinical routine of first-line palliative therapy with P plus T and docetaxel (D) in patients with advanced HER2-positive BC after adjuvant therapy with T, and to determine whether the median PFS of 16.9 months (mos) reported for this subgroup in the CLEOPATRA trial can also be observed in day-to-day routine. Methods: Between 06/2013 through 07/2016, 126 patients with in-label use of P at study start (full-analysis set, FAS) in 81 German hospital-based or outpatient study sites were included into this NIS. Intense documentation period of this NIS was limited to 28 therapy cycles, and a follow-up (FU) for a maximum of 24 mos. Safety was assessed in all patients with at least one dose of P (safety set, SAF, n=132 ). QoL was assessed by FACT-B questionnaire. Main parameter of interest was mPFS. Patient Characteristics: Mean age of FAS patients was 55.1 [30.7 - 80.2] years, 81.7% (95.2%) were below 65 (75) years of age. 51.6% of the FAS patients were hormone-receptor positive (HR+), 91.3% patients of the FAS had distant, 69.8% had visceral, 45.2% liver metastases (VM). 89.7% patients of the FAS had R0-resection, including 44% breast conserving surgery, 42.9% of the FAS received neoadjuvant and 61.9% adjuvant chemo-/immunotherapy and 62.7% prior endocrine treatment. For the FAS median disease-free interval was 40.2 [6.6 - 95.9] mos. Effectiveness results: mPFS of FAS was 18.8 [15.1; 24.2] mos, longest mPFS was documented in patients with non-VM (20.5 [17.7, 27.7] mos), patients < 65 years (19.7 [15.4, 25.7] mos), and HR negative patients (19.4 [13.8, 27.7] mos). Overall response rate in the FAS was documented with 64.3% (55.6; 72.1], with best ORR in HR+ patients (69.2% [57.2, 79.1]), patients with VM (68.2%, [57.9, 77.0] and patients < 65 years (65% [55.5, 73.6]). 46 patients (36.5%) died during the study. Median OS was 55.9 mos [41.2, not reached] for the FAS. Safety: 93.9% of the SAF had an adverse event (AE), 32.6% a serious AE (SAE). AEs related to P occurred in 53.8% of SAF, SAEs related to P were documented in 13.6%. Diarrhea was the most frequently reported related (S)AE. Fatal AEs were seen in 6.1% of the SAF, in 2 patients related to P (death, central nervous system metastases and cerebral disorder). AEs leading to treatment discontinuation of any study product were observed in 20.5% of the SAF. During the intense documentation period, 11 patients had a LVEF <55%. QoL assessment using the total score index, increased slightly over time, however, based on declining patient response rates. Conclusion: Based on results from NIS HELENA, outcomes of pivotal CLEOPATRA study with respect to patients relapsing after adjuvant T pretreatment can be transferred into clinical routine. Patients derived benefit to a variable extent according to predefined subgroups. No new safety signals were detected. Citation Format: Marc Thill, Lead Auth., Andrea Grafe, Peter Klare, Kerstin Luedtke-Heckenkamp, Dietmar Reichert, Pauline Wimberger, Matthias Zaiss, Katja Ziegler-Loehr, Tanja Eckl, Andreas Schneeweiss. Dual HER2-blockade with pertuzumab (P) and trastuzumab (T) in patients with HER2-positive metastatic breast cancer (mBC) relapsing after adjuvant treatment with T. Results from a German non-interventional study (NIS) HELENA (NCT01777958) [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 P2-13-16.

Abstract P3-23-06: Assessment of select HER2-negative metastatic breast cancer (mBC) agents as a proxy to understand health technology assessment bodies uncertainties in HER2-low mBC agents in Germany, France, Spain, Italy and England

Abstract Introduction: Among the molecular subtypes of breast cancer, HER2-negative is the most common, accounting for around ~80% of all cases. Over the last five years, the HER2-negative metastatic breast cancer (mBC) treatment landscape has evolved substantially with European Medicines Agency (EMA) approval of novel therapies for HER2-negative breast cancer as well as with identification of HER2-low disease (HER2 immunohistochemistry 1+ or 2+, but HER2 gene fluorescence in-situ hybridization amplification negative), previously classified as HER2-negative. The majority of new agents targeting HER2-negative/HER2-low breast cancer have been assessed for reimbursement by national health technology assessment bodies (HTABs) in Germany, France, Spain, Italy (EU4) and England. However, paucity/inadequacy of evidence has raised payer concerns over the benefit of these agents leading to restricted or no patient access in some EU markets. This research investigated whether evidence that became available post-launch mitigated HTAB concerns on the evidence base, to support future access to therapies for HER2-low mBC patients. Methods: With the lack of approved HER2-low targeting therapies, an in-depth analysis of the health technology assessments (HTAs) for therapies targeting CDK4/6, PI3K or PARP in HER2-negative mBC was conducted for national HTABs in EU4 and England as a proxy for HER2-low therapies. The analysis included palbociclib, abemaciclib, ribocicblib, alpelisib, talazoparib and olaparib, and focused on HTAB concerns regarding trial design, clinical outcomes, data maturity, safety and health-related quality of life (HRQoL). A targeted literature review (TLR) was conducted to identify evidence published post-HTA submission which addressed priority HTAB concerns and may support clinical outcomes value of future HER2-low mBC agents. Results: Of 53 HTAB recommendations from the 5 included countries, 30% were positive, 23% were positive with restrictions, 17% were negative and 30% received no recommendation. A positive HTAB recommendation opens the path to reimbursement and/or price negotiation depending on the market. In majority of submissions, HTABs questioned relevance of progression- free survival (PFS) as primary endpoint, reliability of median PFS as a surrogate for overall survival (OS) and size of subgroups. Overall, uncertainties around the actual benefit of novel agents were mostly driven by immature OS data at the time of the appraisal and subgroup analyses by molecular factor or prior treatment. The TLR identified studies on the association of PFS to patients’ relevant endpoints, real-world studies validating long-term survival projections and studies confirming the treatment response in subgroups. Conclusions: Majority of HTAB critiques on HER2-negative mBC agents were around study design, selection of endpoints and data maturity and this will likely be the case for upcoming HER2-low therapy launches. In consequence, our research suggests that some uncertainties can be accepted at launch, revealing that post-launch data mitigated some payer concerns. This would ultimately mean that an accelerated access to patients in areas of high unmet need is possible. Citation Format: Thom de Milliano, Tara Harding, Ahmed Seddik, Peter Schmid, Julia Oddsdottir. Assessment of select HER2-negative metastatic breast cancer (mBC) agents as a proxy to understand health technology assessment bodies uncertainties in HER2-low mBC agents in Germany, France, Spain, Italy and England [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 P3-23-06.

Abstract P1-18-19: Long term results with everolimus in advanced hormone receptor positive breast cancer in a multicenter national real world observational study (ESME)

Abstract Background The everolimus (EVE)-exemestane combination has been included in the International guidelines for metastatic HR+/HER2- breast cancer (mBC) since the results of the Bolero-2 trial. Marketing authorization has been granted in France in July 2012. A first report of the UNICANCER Epidemiological Strategy and Medical Economics (ESME) Research program described the real world use of everolimus therapy (ESMO 2017, #266). We report here updated data with long-term overall survival (OS) analyses, focusing on patients treated from 2012 onwards. Methods All patients (pts) who initiated treatment for a newly diagnosed mBC between 2008 and 2017 in all 18 French Comprehensive Cancer Centers have been included in the real life ESME database, which collects retrospective data using a clinical trial-like methodology. The primary endpoint of the present report was overall survival in pts who received everolimus. In order to adjust for differences between groups (EVE treated vs non EVE treated patients), we analyzed the impact of everolimus on OS and PFS by using a propensity score and inverse probability of treatment weighting (IPTW) sensitivity analyses, built with relevant cancer-related clinical variables in relation to survival and allocation of treatment. Those analyses were performed by line 1, 2 or 3 of treatment for mBC. Results The ESME program included 23,698 pts of whom 1897 with HR+/HER2- mBC received at least 1 dose of EVE and were diagnosed after 2012. Median age was 63 y (22-103). EVE pts were slightly younger than non-EVE pts (25.9% and 23.7% under 52 y, respectively, p=0.0574). EVE treated pts had more frequent non visceral metastases (52.3% vs 47.9%) and bone only metastases (38.5% vs 31.3%) at metastatic diagnosis, and less symptoms at mBC diagnosis (42.4% vs 47.5%) than non-EVE pts (all p values <.001). 94.3% of EVE pts had received an EVE-exemestane combination. EVE was administered either in the 1st, 2nd or 3rd line+ setting, in 3.3%, 14.7% and 25.3% of all cases respectively. At each line, treatments in the non-EVE treated pts included various endocrine therapy or chemotherapy regimen. Median follow-up was 47.9 m (0-98.7), and 61.4 m (2.1-98.7) for the overall- and EVE treated populations, respectively. Crude and landmark (6 and 12 months) OS analyses all suggested a longer OS with EVE based therapy. IPTW analyses by lines of treatment, comparing EVE-treated and non-EVE-treated patients, suggested a longer progression free survival with EVE when administered in the 3rd line setting (HR=0.82 CI95% [0.745-0.903], p<.0001). IPTW analyses consistently showed a significantly longer OS with EVE based treatment when administered in lines 1, 2 and 3 with respective HR values of 0.34, 0.34 and 0.23 (Table). Causes for EVE discontinuation were mainly disease progression (54%) and toxicity (26.6%). An exploratory analysis showed that 998 EVE treated patients (52.6%) also received a CDK4/6 inhibitor based treatment, mostly after EVE therapy (n=826, 82.8%). Median duration of CDK4/6 inhibitor therapy for those patients was 4.6 months (IQR 2.9-8.7). Conclusions These results are limited by the retrospective nature of the study and the lack of performance status, comorbidity or nutritional data. However, the long-term follow up of the ESME database suggests a favorable association between everolimus therapy and overall survival in HR+, HER2- mBC, persistent after IPTW adjusted analyses. HR (CI95%)p value12 months OS EVE vs not (unadjusted Kaplan Meier)Line 10.34 (0.16-072).005497% vs 93%Line 20.34 (0.22-0.52)<.000194% vs 85%Line 30.23 (0.14-0.36)<.000195% vs 79% Citation Format: Hélène Francois-Martin, Audrey Lardy-Cleaud, Barbara Pistilli, Christelle Levy, Véronique Diéras, Jean-Sébastien Frenel, Séverine Guiu, Marie-Ange Mouret-Reynier, Audrey Mailliez, Jean-Christophe Eymard, Thierry Petit, Mony Ung, Isabelle Desmoulins, Paule Augereau, Thomas Bachelot, Lionel Uwer, Marc Debled, Jean-Marc Ferrero, Corinne Veyret, Antony Goncalves, Michael Chevrot, Paul H Cottu. Long term results with everolimus in advanced hormone receptor positive breast cancer in a multicenter national real world observational study (ESME) [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 P1-18-19.

Abstract P2-13-27: Infusion-related reactions in patients receiving pertuzumab and trastuzumab: A retrospective study

Abstract BACKGROUND: The use of two anti-HER2 monoclonal antibodies (mAbs) (pertuzumab and trastuzumab) combined with taxanes is the standard of care for first line treatment in HER2-positive metastatic breast cancer (mBC). Infusion related reactions (IRR) during first administration of anti-HER2 mAb have been reported. Reintroduction of the causal drugs is often possible, but there is no data to identify patients at highest risk of developing IRR and modalities of safe reintroduction. The aim of this study was to report patients who experienced IRR during anti-HER2 mAbs infusions at Institut Curie Hospitals (ICH) and to describe these reactions. METHODS: All IRR cases must be reported to the ICH pharmacies. We retrospectively inspected the electronic record of patients who experienced an IRR during pertuzumab (Pmab) and trastuzumab (Tmab). We collected patients’ characteristics, grade of IRR and outcomes. RESULTS: From January 2013 to December 2020, a total of 223 patients had at least one Pmab+Tmab infusion as part of their BC treatment. Among them, 28 patients (8%) with anti-HER2 mAb IRR were identified. All patients but one had an HER2-positive BC; the HER2-negative case was a HER3-mutant mBC. Twelve patients (43%) had de novo mBC. Twenty-six patients (93%) received Pmab+Tmab as first line treatment for mBC. Ten patients were previously exposed to Tmab and three to Pmab+Tmab for (neo)adjuvant treatment. At IRR onset, 21 patients (75%) had liver metastasis, with more than five liver metastases for 19 of them. Fifteen patients (55%) had liver enzymes upper normal limit. IRR occurred during first anti-HER2-mAb infusion in 22 patients (79%) despite pre-treatment with antihistaminic and/or glucosteroids for taxanes. The other IRR were reported at the 2nd, 5th, 6th, 8th and > 10th cycle of Pmab+Tmab. Sixteen IRR (57%) were attributed to Pmab infusion, 9 (32%) to Tmab infusion and 3 (11%) to Tmab and/or Pmab. Al IRR were declared to the pharmacovigilance agency. Majority of reactions were mild to moderate (54% of grade 2). Most frequent symptoms associated with IRR were: thrills (68%), hyperthermia (64%); low oxygen saturation (36%), pain (25%), hypotension (21%), cutaneous (18%) and digestive (18%) reaction. Three patients were transferred to ICU. One death was attributed to anti-HER2 mAb IRR (death was attributed to respiratory distress during the first Tmab infusion). Reintroduction off Pmab+Tmab was performed in 18 patients, after pre-treatment with antihistaminic and/or glucosteroids and with vital function monitoring in conventional hospitalization. No recurrence of IRR was observed in 15/18 patients. For the 3 patients with recurrent IRR, symptoms were mild to moderate. Objective response to anti-HER2 treatments was observed in twenty three patients (82%; 8 complete responses; 15 partial responses). Median PFS was 16 months. CONCLUSIONS: Most anti-Her2-mAb IRR occurs during first infusion, are mild to moderate and do not require a transfer in ICU. Our study suggests that patients with high liver burden might be over-represented among those experiencing an IRR. Reintroduction of Pmab+Tmab was safe in most patients, allowing the continuation of the anti-HER2 dual blockade. Citation Format: Delphine Loirat, Juliette Logeart, Pauline Vaflard, Aurélien Noret, Mathilde Saint-Ghislain, Edith Borcoman, Audrey Hurgon, Cyrille Cros, Thomas Genevee, Audrey Bellesoeur, Francesco Ricci, Florence Lerebours, Laurence Escalup, Marie-Paule Sablin, François-Clément Bidard, Paul H. Cottu, Jean-Yves Pierga. Infusion-related reactions in patients receiving pertuzumab and trastuzumab: A retrospective 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 P2-13-27.

Abstract P5-14-18: Socioeconomic and geographic barriers affect rates of standard of care therapy utilization in patients with hormone receptor positive, HER2 negative metastatic breast cancer

Abstract Background: It is of value to determine whether treatment disparities exist in the management of hormone receptor positive (HR+), HER2 negative (HER2-) MBC due to location, age, gender, practice type, or payment methods. The objective of this study was to evaluate prescription patterns for CDK46 inhibitors (CDKI) in the first line setting in patients with HR+ HER2- MBC at the University of Pittsburgh Medical Center (UPMC), a tertiary care academic center with a large satellite clinic network. Methods: Data were obtained using a quality care insight tool (QCIT, Pfizer) which provided information regarding MBC treatment utilization patterns using the pharmacy and medical claims data from the IQVIA Anonymized Patient Longitudinal Dataset. This data set includes HIPAA-compliant anonymized information on diagnostic codes, tests, prescribed treatments, and procedures for 17.9 million US cancer patients from 2012 onward. Analysis was focused on a comparison of a UPMC patient cohort to a national cohort of patients with HR+/HER2- MBC to better understand local prescription patterns. Inferential statistical analysis was not applicable to data obtained from the QCIT tool and thus was not performed. Inclusion criteria included (1) patients ≥ 18 years of age on first breast cancer occurrence; (2) medical claim indicating HR+ breast cancer and the absence of HER2 positivity; and/or (3) a pharmacy claim for a CDKI; and (4) at least one medical or pharmacy claim six months before and six months after MBC diagnosis and CDKI prescription. Results: Comparison of national treatment prescription patterns to treatments utilized at UPMC facilities for patients with HR+ HER2- MBC in the first-line setting demonstrated higher rates of CDKI-based therapy utilization within UPMC institutions comparatively (61% vs. 54%, respectively). Rates of chemotherapy use in the UPMC population were concordantly lower than the national average (1% vs. 5%). The rate of CDKI-based therapy utilization in MBC patients in the first line was higher at urban UPMC sites vs. their rural counterparts (82% vs. 70%). Patients with Medicare showed notably lower CDKI utilization rates compared to their counterparts receiving Medicaid (43% vs 83%) or commercial third-party insurance (43% vs. 63%). Conclusions: Higher rates of CDKI utilization in the first-line metastatic setting indicate more widespread adoption of first line CDKI at UPMC (a tertiary health care system with a large community satellite network) as compared to national averages. Within the UPMC patient population, lower rates of first line CDKI utilization in patients receiving Medicare or in rural areas may be reflective of socioeconomic obstacles, which limit patient access to care. Further research is planned to investigate possible clinical or social determinants of these differences. Citation Format: Christopher DeHaven, Azadeh Nasrazadani, Adam Brufsky. Socioeconomic and geographic barriers affect rates of standard of care therapy utilization in patients with hormone receptor positive, HER2 negative metastatic breast cancer [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 P5-14-18.

Innovations in practice. 5 years of palbociclib experience in the Russian Federation. Overview of web-conference took place on 8 October 2021

The educational cycle "Venus of The Future: the discoveries and new traditions in the treatment of mBC" was initiated by Pfizer with the support of TS Oncology. During several web-conferences planned in 20212022 key experts discussed implementation in clinical practice and availability of innovative approaches for treatment patients with HER-negative mBC in the Russian Federation. The first web-conference of the cycle - "Innovations in practice. 5 years of palbociclib experience in the Russian Federation" took place on October 8, 2021 and was dedicated to the 5th anniversary since registration in the Russian Federation of palbociclib 1st CDK4/6 inhibitor (CDK4/6i) in our country. Key Russian experts in oncology, who were at the forefront of introducing CDK4/6i into routine clinical practice, took part in the event and outlined the importance of considering the differences among iCDK 4/6 in terms of the tolerance profile and monitoring requirements, as well as taking into account practical experience when making desicion to choose specific product. Experts agreed that palbociclib have a great advantage over other products in the class due to significant amount of RCT and RWE data, as well as broad practical experience (more than 5 years) in the Russian Federation and in the world.

289P A retrospective population-based observational study in metastatic HER2-positive breast cancer patients in Denmark previously treated with T-DM1

Current Danish guidelines in HER2-positive metastatic breast cancer (mBC) recommend the combination of trastuzumab with one of several chemotherapeutic agents for 3rd line or later treatments. This study aims to describe treatment of HER2-positive mBC in 3rd line or later after previous treatment with T-DM1 for mBC in a Danish real-world setting.

Metabolite Biomarkers of Response (BoRs): Towards a fingerprint for the evolution of metastatic breast cancer

Breast cancer is the most common cancer in women worldwide and despite improved treatment strategies, it persists as the second leading cause of death of women globally. Overall prognosis drops drastically once the cancer has metastasized, which is also associated with resistance to therapy. The evolution from a localized breast cancer to metastatic disease is complex and multifactorial. Metabolic reprogramming is a pre-requisite for this transition. In this graphical review, we provide an overview of altered metabolic pathways observed in metastatic breast cancer (mBC) and detail how metabolite biomarkers could serve as a novel class of precision medicine tools to improve the diagnosis, monitoring, and treatment of mBC.

Projecting the Prevalence and Costs of Metastatic Breast Cancer From 2015 through 2030.

BackgroundThis study projected the number of metastatic breast cancer (mBC) cases and costs (medical and productivity) attributable to mBC through 2030 among 3 age groups: younger (aged 18-44 years), midlife (aged 45-64 years), and older women (aged 65 years and older).MethodsWe developed a stock/flow model in which women enter the mBC population at initial diagnosis (de novo stage IV) or through progression of an earlier-stage cancer. Women exit the mBC population through death. Input parameters by age and phase of treatment came from the US Census, Surveillance, Epidemiology, and End Results and peer-reviewed literature.ResultsIn 2030, we estimated there would be 246 194 prevalent cases of mBC, an increase of 54.8% from the 2015 estimate of 158 997. We estimated total costs (medical and productivity) of mBC across all age groups and phases of care were $63.4 billion (95% sensitivity range = $59.4-$67.4 billion) in 2015 and would increase to $152.4 billion (95% sensitivity range = $111.6-$220.4 billion) in 2030, an increase of 140%. Trends in estimated costs were higher for younger and midlife women than for older women.ConclusionsThe cost of mBC could increase substantially in the coming decade, especially among younger and midlife women. Although accounting for trends in incidence, progression, and survival, our model did not attempt to forecast structural changes such as technological innovations in breast cancer treatment and health-care delivery reforms. These findings can motivate early detection activities, direct value-driven mBC treatment, and provide a useful baseline against which to measure the effect of prevention and treatment efforts.

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond

ABSTRACT Introduction Despite the substantial improvements made in human epidermal growth factor receptor 2 (HER2)–targeted therapies since the approval of trastuzumab more than 20 years ago, there is still considerable unmet need in patients with HER2-expressing breast cancer (BC) and other solid tumors. Trastuzumab deruxtecan (T-DXd) is a newer antibody-drug conjugate approved for the treatment of metastatic breast cancer (BC) and gastric cancer (GC) and is under active investigation in other solid tumors, including non–small cell lung cancer, colorectal cancer, and HER2-low tumors. Areas covered The current treatment and investigational landscape of HER2-positive and HER2-low metastatic BC (mBC) and the preclinical and clinical trials investigating T-DXd. To identify relevant literature, a search was performed on English-language publications and congress abstracts. Expert opinion T-DXd is likely to become the standard of care for second-line treatment of HER2-positive mBC, and it may play a role in the treatment of hormone receptor–positive and triple-negative mBC with HER2-low expression. Because it was recently approved in the United States and Japan to treat HER2-positive metastatic GC, it holds promise for the treatment of other HER2-positive solid tumors, including colorectal cancer, non–small cell lung cancer, and HER2-low BC.

The cost-effectiveness of atezolizumab in first-line for metastatic triple negative breast cancer is heavily linked to PD-L1 level.

The present analysis was conducted to assess the pharmacological costs of atezolizumab as first-line treatment in triple negative metastatic breast cancer (mBC). Pivotal phase III randomized controlled trial (RCT) was considered. Nine hundred and two patients were included. Differences in costs between the 2 arms (atezolizumab plus nabpaclitaxel versus placebo plus nab-paclitaxel) was 17 398 €, with a cost of 7564 €per month of OS-gain in the overall population and 2485 €per month of OS-gain in PD-L1-positive (≥1) population. Combining pharmacological costs of drugs with the measure of efficacy represented by the OS, atezolizumab could be considered cost-effective in first-line treatment for triple-negative mBC only in PD-L1-positive population, but a reduction of costs is mandatory.

Radioembolization in Metastatic Breast Cancer

AbstractMetastatic breast cancer (MBC) remains the second cause of cancer death in women, despite improvements in early breast cancer detection and treatments, with a 5-year survival of only 27%. Patients with MBC involving the liver have a 5-year survival of only 3.8 to 12%. Systemic therapy is the cornerstone for the treatment of MBC according to the National Comprehensive Cancer Network (NCCN) guidelines. Radioembolization is not specifically prescribed by the NCCN guidelines in the treatment of MBC liver metastasis, but is an emerging therapy with some promising results. The two primary reasons to offer radioembolization would be to prolong life and to palliate and improve quality of life. We review here the indications, contraindications, technique, case examples, and unanswered questions.

Exploring the concepts and practices of advanced breast cancer treatment: a narrative review.

ObjectiveTo explore the concepts and practices of advanced breast cancer treatment.BackgroundMetastatic breast cancer (MBC) has become a chronic disease, with a median overall survival (OS) of around 3 years and a 5-year survival rate of about 25%. OS are strongly associated with the best available care, which consists of not only application of guidelines, but also multidisciplinary specialized care, the most efficacious medicines, and so on. Advanced breast cancer (ABC) Guidelines are the most important and authoritative guidelines for MBC.MethodsIn this review, we demonstrate the history and evolution of the global ABC Guidelines. Since 2015, Chinese multidisciplinary experts have drafted guidelines for clinical diagnosis and treatment of MBC. All of these ABC guidelines describe specialized therapeutic principles for different subtypes MBC in detail. Encouragingly, we have found that some special subtypes are hopeful of being cured, such as HER-2 positive patients with low tumor burden or HR-positive (HR+) MBC with non-visceral metastasis. In our opinion, the definition of cure of MBC is that MBC patients achieve CR and remain for more than five years after systemic treatment, including those with local therapy. Consequently, we also have conducted some researches and meaningful explorations in different subtypes of MBC. In HER2 positive MBC, our study revealed that regular HER2 circulating extracellular domain (ECD) assay can provide the real-time monitoring of tumor burden and prediction of poor outcome, and may present an important opportunity to reassess HER2 status. In HR+ MBC, we suggested that hormone therapy (HT) maintenance is the priority choice for HR+/HER2− MBC after first-line combined chemotherapy. Besides, our real-world study revealed that fulvestrant combined with ovarian suppression was an active option for premenopausal HR+/HER2- MBC. And also, we observed that everolimus (low-dose) combined with hormone therapy was still effective for HR+/HER2− MBC. For mTNBC patients, we found that THA and endostatin exhibited potential efficacy and was well tolerated in pretreated patients.ConclusionsOur concepts and practices will contribute to the design of relevant clinical research and accumulation of evidence, and cure of MBC is promising.