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Nursing Strategies to Optimize Treatment Experiences in Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer

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Nursing Strategies to Optimize Treatment Experiences in Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer

  1. 1. Nursing Strategies to Optimize Treatment Experiences in Hormone-Receptor Positive, HER2-Negative Metastatic Breast Cancer Constance Visovsky, PhD, RN, ACNP, FAAN Associate Professor, College of Nursing University of South Florida
  2. 2. Disclosures Dr. Visovsky has no relevant financial relationships to disclose.
  3. 3. Learning Objectives Describe patient- and disease-related factors that can inform individualized treatment planning in HR- positive, HER2-negative MBC Differentiate therapeutic and safety profiles of CDK4/6 inhibitors in HR-positive, HER2-negative MBC Apply supportive care strategies to mitigate adverse events associated with CDK4/6 inhibitors and promote adherence to therapy HR = hormone receptor; HER2 = human epidermal growth factor receptor 2; MBC = metastatic breast cancer; CDK = cyclin dependent kinase.
  4. 4. HR-Positive, HER2-Negative MBC: Scope of the Problem Mariotto et al, 2017. Approximately 3,500,000 women in the US are living with breast cancer The prevalence of women with MBC is estimated to be 154,794 28% diagnosed with de novo stage IV disease Younger women with de novo disease have higher survival rates than older women 72% progressed to stage IV since diagnosis The prevalence of MBC has increased over time: 4% (1990-2000) 17% (2000-2010) 31% (2010-2020)
  5. 5. Estimations of MBC Prevalence Mariotto et al, 2017.
  6. 6. Prevalence of MBC Cases (2017) Mariotto et al, 2017.
  7. 7. Treatment Goals for Patients with MBC Need to balance treatment efficacy with toxicity Improve survival Delay PFS Prolong duration of response Symptom palliation Improve (or maintain) QOL PFS = progression-free survival; QOL = quality of life. Cardoso et al, 2017.
  8. 8. Breast Cancer Pathophysiology: Scientific Foundation for CDK4/6 Inhibitors Finn, Aleshin et al, 2016. Traditional endocrine therapy and/or chemotherapy has long been the treatment of choice for HR+, HER2– MBC New understanding of the molecular diversity of breast cancer, and resistance to endocrine therapy has led to the development of targeted agents Targeted agents have fewer toxicities and increased efficacy
  9. 9. Breast Cancer Pathophysiology: Scientific Foundation for CDK4/6 Inhibitors (cont.) P = phosphate; RB = retinoblastoma protein. Finn, Aleshin et al, 2016; Mok et al, 2018; Phadke & Thomas, 2014. CDKs are important regulators of cell division Amplification (increased copies) of CDK4 and cyclin D1 have been implicated in 15-25% of all breast cancers Overexpression (increased gene transcription) of cyclin D1 is reported in >50% of all breast cancers Cyclin D1 amplification is found most frequently in luminal A (29%), B (58%), and HER2+ (38%) subtypes
  10. 10. Breast Cancer Pathophysiology: CDK4/6 and Cell Cycle Control pRb = phosphorylation of retinoblastoma. Peurala et al, 2013. Cell cycle progression is regulated at specific checkpoints by cyclins and associated CDKs pRb represses cell cycle progression When turned on by D1 CDK4/6 complexes, cells are committed to G1-S progression in the cell cycle, bypassing the restriction point
  11. 11. Breast Cancer Pathophysiology: CDK4/6 and Cell Cycle Control (cont.) Phadke & Thomas, 2014; Suryadinata et al, 2010.
  12. 12. Mechanism of Action of CDK4/6 Inhibitors Corona & Generali, 2018.
  13. 13. CDK4/6 Inhibitors: What Do We Know?
  14. 14. CDK4/6 Inhibitor Phase 3 Studies qd = once daily. Finn, Martin et al, 2016; Hortobagyi et al, 2016. PALOMA-2 Palbociclib 125 mg qd 3 weeks on/1 week off 2:1 randomized MONALEESA-2 Ribociclib 600 mg qd 3 weeks on/1 week off 1:1 randomized
  15. 15. CDK4/6 Inhibitor Phase 3 Studies (cont.) Primary end point: PFS (locally assessed per RECIST v1.1) Secondary end points: OS, ORR, CBR, Safety • Postmenopausal women • HR+/HER2–a • Metastatic breast cancer • No prior therapy for advanced disease • AI-resistant patients excluded CDK4/6 inhibitor 3 weeks on/1 week off Placebo + Letrozole aER+ in PALOMA-2. AI = aromatase inhibitor; CBR = clinical benefit rate; ORR = overall response rate; OS = overall survival. Finn, Martin et al, 2016; Hortobagyi et al, 2016.
  16. 16. PALOMA-2: Palbociclib Efficacy and Safety aIn patients with measurable disease. CI = confidence interval; HR = hazard ratio; AE = adverse event. Finn, Martin et al, 2016. Palbociclib + Letrozole Placebo + Letrozole HR (95% CI) P Value Median PFS, mo 24.8 14.5 0.58 (0.46, 0.72) <.001 ORRa, % 55.3 44.4 – – Most common grade 3/4 AEs with palbociclib + letrozole: Neutropenia (66%) Leukopenia (25%) Anemia (5%) Fatigue (2%)
  17. 17. MONALEESA-2: Ribociclib Efficacy Hortobagyi et al, 2016.
  18. 18. MONALEESA-2: Ribociclib Safety ALT = alanine aminotransferase. O’Shaughnessy et al, 2018; Hortobagyi et al, 2016. Most common grade 3/4 AEs with ribociclib + letrozole: Neutropenia (59%) Leukopenia (21%) Hypertension (10%) Increased ALT (9%)
  19. 19. MONARCH 2 Trial: Fulvestrant + Abemaciclib Patients with HR-positive, HER2-negative MBC, who have relapsed or progressed after endocrine therapy (N=669) Abemaciclib PO 150 mg BID in 28 day cycles plus fulvestrant IM 250 mg Q2W x 1 then Q4W (n=446) Placebo plus fulvestrant IM 250 mg Q2W x 1 then Q4W (n=223) BID = twice a day; IM = intramuscular; PO = by mouth; Q2W = every 2 weeks; Q4W = every 4 weeks. Sledge et al, 2017.
  20. 20. MONARCH 2 Trial: Fulvestrant + Abemaciclib (cont.) aIn patients with measurable disease. Sledge et al, 2017. Abemaciclib + Fulvestrant Placebo + Fulvestrant HR (95% CI) P Value Median PFS, mo 16.4 9.3 0.55 (0.45, 0.68) <.001 ORRa, % 48.1 21.3 – – Most common AEs (all grades) with abemaciclib + fulvestrant: Diarrhea (86%) Neutropenia (46%) Nausea (45%) Fatigue (40%)
  21. 21. Treatment Options for HR+, HER2– MBC Selection of treatment for specific patients: Endocrine therapy only (tamoxifen, AI, fulvestrant) Endocrine therapy plus palbociclib, ribociclib, abemaciclib, or everolimus Chemotherapy single agent/combination Clinical trial of new agent Cardoso et al, 2017.
  22. 22. Individualized Treatment Selection ECOG = Eastern Cooperative Oncology Group. NCCN, 2018. Menopausal status Post-menopausal women, HR+, HER2– Performance Status ECOG 0-1 Disease site(s) Advanced or metastatic disease; luminal breast cancer Disease-free interval length of time to progression Prior (neo)adjuvant hormonal therapy Prior therapy (hormonal or taxane-based chemotherapy) No prior systemic therapy
  23. 23. Therapeutic Profiles of CDK4/6 Inhibitors De novo disease Post-menopausal women with de novo HR+, HER2– disease receiving ET plus CDK4/6 inhibitors demonstrated prolonged PFS compared with ET alone Inherent differences in tumor biology may exist in de novo versus relapsed BC Overall survival analyses are needed to determine the long-term benefit of adding CDK4/6 inhibitors to first-line ET therapy Recurrent disease Endocrine therapy plus CDK4/6 inhibitor is the first-line treatment option in post-menopausal women with recurrent HR+, HER2– MBC Further research is needed to determine the optimal treatment sequencing of CDK4/6 inhibitors in the second-line treatment setting, as current data are from patients who received no prior CDK4/6-based therapy ET = endocrine therapy. O’Shaughnessy et al, 2018; Cardoso et al, 2016.
  24. 24. Nursing Strategies to Optimize Treatment Experiences
  25. 25. Monitoring Treatment-Related Toxicities CBC = complete blood count; CT = computed tomography; ECG = electrocardiogram; GI = gastrointestinal; LFT = liver function test; N & V = nausea and vomiting; VQ = ventilation-perfusion. Sammons et al, 2017. Hematologic Toxicity GI Toxicity Liver Toxicity QT Pulmonary Embolism Symptoms Shortness of breath, fatigue, bleeding, Diarrhea, N & V Jaundice, weight loss, dark urine, itching, abdominal swelling Palpitations, syncope Chest pain, shortness of breath, cough, tachypnea, tachycardia Assessment CBC Electrolytes + magnesium supplementation LFTs ECG Monitor symptoms; CT, VQ scan Crucial Time 14 days after treatment start cycles 1 & 2 (palbociclib, ribociclib) 1 week after start treatment (abemaciclib) Throughout treatment First 4 weeks Throughout treatment Frequency Baseline, treatment cycle start, and day 14 cycles 1, 2 Throughout treatment Throughout treatment Throughout treatment Throughout treatment
  26. 26. Managing Treatment-Related Toxicities Sammons et al, 2017. Leukopenia & neutropenia ASCO suggests checking CBC: Prior to beginning a CDK4/6 inhibitor At the beginning of each new cycle On day 14 of cycles 1 and 2 Reversible with dose reduction or interruption, resolving in ~7 days GI toxicity If infection is ruled out, the patient can begin antidiarrheal agents Loperamide or diphenoxylate/atropine Assess for signs of dehydration and electrolyte loss
  27. 27. Managing Treatment-Related Toxicities (cont.) Sammons et al, 2017. Cardiac toxicity ECG should be performed at baseline Avoid coadministration of medications that can increase QT interval Monitor serum potassium and sodium, especially in patients with diarrhea or vomiting Thromboembolic events Monitor for shortness of breath, hypoxia, chest pain, rapid breathing, and tachycardia Patients should report episodes of fainting, lightheadedness, and sweating
  28. 28. Patient Teaching Sammons et al, 2017. General information Take the dose at the same time each day If a dose is missed, take the next scheduled dose Do not double up dosages Palbociclib must be taken with food Ribociclib and abemaciclib can be taken with or without food Abemaciclib requires twice daily dosing
  29. 29. Patient Teaching (cont.) Sammons et al, 2017. Neutropenia Timely monitoring of CBC High level of personal hygiene Avoid crowds and those with infections Report fever >38.3o C or persistent fever >38o C lasting 1 hour or more
  30. 30. Patient Teaching (cont.) OTC = over-the-counter. Sammons et al, 2017. GI/liver Report diarrhea as soon as it occurs to prevent dehydration and electrolyte imbalances Report all OTC medications, including herbal supplements to avoid liver dysfunction Limit alcohol intake Report presence of weight loss, dark urine, jaundice, abdominal swelling, or pain
  31. 31. Patient Teaching (cont.) Sammons et al, 2017. Pulmonary embolism Report chest pain, shortness of breath, rapid heart rate, or rapid breathing Report fainting, lightheadedness, or sweating Even large emboli can present as hypotension QT prolongation Report palpitations and/or any episodes of fainting
  32. 32. Promoting Adherence to Therapy Banning, 2012; Geynisman et al, 2013; Spoelstra & Given, 2011. Oral targeted therapies represent ~30% drugs in the oncology pipeline The patient/family now control timing, dose, frequency of oncology drug administration, and adherence to treatment regimen There is no gold-standard technique to quantify adherence 80% adherence considered an acceptable standard, but is this enough for molecularly- targeted agents? Will <100% adherence result in treatment failure and patient death?
  33. 33. Promoting Adherence to Therapy (cont.) For other chronic illnesses, barriers to medication adherence have been identified: Cost/SES Patient literacy Health beliefs Social support Psychological state Regimen complexity Side effects and food/drug interactions SES = socioeconomic status. Given et al, 2011; Banning, 2012; Geynisman et al, 2013; Spoelstra & Given, 2011.
  34. 34. Promoting Adherence to Therapy: Addressing Barriers Given et al, 2011; Banning, 2012; Geynisman et al, 2013; Spoelstra & Given, 2011. Address cost through assistance programs Help patients apply Ensure timely refills Assist patient with memory triggers Alarms, pill boxes, calendar Institute nurse-led telephone support-automated reminders ONS oral adherence toolkit
  35. 35. Promoting Adherence to Therapy: Addressing Barriers (cont.) Given et al, 2011; Banning, 2012; Geynisman et al, 2013; Spoelstra & Given, 2011. Educate the patient at each visit/interaction Obtain or create health literature at the 8th- grade reading level Refer to MBC support groups Make the patient a member of the care team
  36. 36. Psychosocial Support Lewis et al, 2015; Sammons et al, 2017. Refer patients to national MBC advocacy groups and networks to build community and support Keep disease control and QOL at the forefront of treatment decisions Educate patients and families about the nature of MBC, goals of treatment, and treatment options Educate patients/families about CDK4/6 inhibitors Emphasize adherence, side effects, adverse effects, missed doses, and self-care Provide resources for financial support
  37. 37. Case Study AC plus T = doxorubicin and cyclophosphamide followed by paclitaxel; EBRT = external beam radiation therapy. A 60-year-old woman presented with a left breast mass (3x3.5) in 2012 She underwent lumpectomy with axillary node examination (N0). Tumor: ER+, PR+, HER2– She then received dose-dense AC plus T, followed by 6 weeks of EBRT She completed 5 years of an AI in 2017 In May 2018, she noted back pain and right quadrant abdominal discomfort Several small but measurable lesions to the liver and metastases to the lumbar spine were found
  38. 38. Case Study (cont.) Would this patient be eligible for treatment with a CDK4/6 inhibitor? What considerations would influence the choice of CDK4/6 inhibitor? What assessments and monitoring should be instituted? What supportive care planning may be needed for this patient?
  39. 39. Key Learning Takeaways Cardoso et al, 2017; NCCN, 2018. Endocrine therapy is the first-line treatment of HR+, HER2– MBC Fulvestrant may also be considered in first-line therapy Endocrine therapy plus a CDK4/6 inhibitor is the first-line treatment option in both de novo and post- menopausal women with recurrent HR+, HER2– advanced or metastatic breast cancer
  40. 40. Key Learning Takeaways (cont.) Cardoso et al, 2017; NCCN, 2018. Plan of care must include patient and family teaching concerning expected side effects, reporting of adverse effects, and expected self- management strategies Proactive recommended monitoring of complete blood counts, liver enzymes, ECG recordings, and patient symptoms can prevent or permit early detection of AEs Strategies to enhance patient compliance with treatment and monitoring intervals should be utilized
  41. 41. Key Learning Takeaways (cont.) Cardoso et al, 2017; NCCN, 2018. Treatment considerations in disease progression Prior treatments received/response achieved Extent of disease Performance status Toxicity profile Data are insufficient to answer questions of treatment sequencing for second-line treatment after disease progression Although PFS is significantly improved for patients on CDK4/6 inhibitors, data for OS is lacking Additional research is needed to understand the pathways of endocrine resistance
  42. 42. References Banning M (2012). Adherence to adjuvant therapy in post-menopausal breast cancer patients: a review. Eur J Cancer Care (Engl), 21(1):10-19. DOI:10.111/j.1365-2354.2011.01295.x Cardoso F, Costa A, Senkus E, et al (2017). 3rd ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 3). Ann Oncol, 28(1):16-33. DOI:10.1093/annonc/mdw544 Corona SP & Generali D (2018). Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2– advanced breast cancer. Drug Des Devel Ther, 12:321-330. DOI:10.2147/DDDT.S137783 Finn RS, Aleshin A & Slamon DJ (2016). Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res, 18(1):17. DOI:10.1186/s13058-015-0661-5 Finn RS, Martin M, Rugo HS, et al (2016). Palbociclib and letrozole in advanced breast cancer. N Engl J Med, 375:1925-1936. DOI:10.1056/NEJMoal607303 Geynisman DM & Wickersham KE (2013). Adherence to targeted oral anticancer medications. Discov Med, 15(83):231-241. Given BA, Spoelstra SL & Grant M (2011). The challenges of oral agents as antineoplastic treatments. Semin Oncol Nurs, 27(2):93-103. DOI:10.1016/j.soncs.2011.02.003 Hortobagyi GN, Stemmer SM, Burris HA, et al (2016). Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med, 375(18):1738-1748. Lewis S, Yee J, Kilbreath S & Willis K (2015). A qualitative study of women’s experiences of healthcare, treatment and supportive care for metastatic breast cancer. Breast, 24(3):242-247. DOI:10.1016/j.breast.2015.02.025 Mariotto AB, Etzioni R, Hurlbert M, et al (2017). Estimation of the number of women living with metastatic breast cancer in the United States. Cancer Epidemiol Biomarkers Prev, 26(6):809-815. DOI:10.1158/1055-9965.EPI-16-0889 Mok MT, Zhou J, Tang W, et al (2018). CCRK is a novel signaling hub exploitable in cancer immunotherapy. J Cell Physiol, 186:138-151. DOI:10.1016/j.pharmthera.2018.01.008 National Comprehensive Cancer Network (2018). NCCN Clinical Practice Guidelines in Oncology: breast cancer. Version 3.2018. Available at: http://www.nccn.org O’Shaughnessy J, Petrakova K, Sonke GS, et al (2017). Ribociclib plus letrozole versus letrozole alone in patients with de novo HR+, HER2– advanced breast cancer in the randomized MONALEESA-2 trial. Breast Cancer Res Treat, 168:127. DOI:10.1007/s10549-017-4518-8 Peurala E, Koivunen P, Haapasaari KM, et al (2013). The prognostic significance and value of cyclin D1, CDK4 and p16 in human breast cancer. Breast Cancer Res, 15(1):R5. DOI:10.1186/bcr3376
  43. 43. References Phadke S & Thomas A (2014). Targeting cell cycle progression: CDK4/6 inhibition in breast cancer. Available at: https://www.onclive.com/publications/contemporary-oncology/2014/november-2014/targeting-cell-cycle-progression-cdk46-inhibition-in- breast-cancer?p=1 Sammons SL, Topping DL & Blackwell KL (2017). HR+, HER2– advanced breast cancer and CDK4/6 inhibitors: mode of action, clinical activity, and safety profiles. Current Cancer Drug Targets, 17:637-649. Sledge GW, Toi M, Neven P, et al (2017). MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2–advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol, 35(25):2875-2884. DOI:10.1200/JCO.2017.73.7585 Spoelstra SL & Given CW (2011). Assessment and measurement of adherence to oral antineoplastic agents. Semin Oncol Nurs, 27(2):116-132. DOI:10.1016/j.soncn.2011.02.004 Suryadinata R, Sadowski M & Sarcevic B (2010). Control of cell cycle progression by phosphorylation of cyclin-dependent kinase (CDK) substrates. Biosci Rep, 30:243-255. DOI:10.1042/BSR20090171

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