Targeted Therapy Management in HR+ Metastatic Breast Cancer
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Read these 3 case studies on the advanced practitioner’s role in determining treatment for patients with HR-positive metastatic breast cancer based on their molecular profile and in managing adverse effects from treatment with targeted therapies. These cases were curated by Melissa Rikal, FNP-BC, AOCNP®, of Sarah Cannon Research Institute.
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Answer the poll next to each case to see how your colleagues are managing similar practical situations. You will be able to see all results in real time.
Treatment Selection Based on Molecular Profile
Clinical Pearl: There are multiple options for second-line endocrine therapy and treatment selection is often based on numerous factors including actionable mutations, prior therapy, patient comorbidities, anticipated oral adherence, goals of care, and lifestyle factors.
A.M. is a 55-year-old African American female with a 5.7-cm right upper outer quadrant mass on diagnostic mammogram and ultrasound. Right breast biopsy revealed an invasive ductal carcinoma, grade 2, ER 95%, PR 75%, HER2 IHC 1+. She underwent bilateral mastectomy, which revealed multi-focal disease with a 22-mm and 32-mm invasive component and four positive nodes. CT and bone scan completed after surgery did not reveal evidence of metastatic disease and she went on to receive six cycles of Taxotere, Adriamycin, and cyclophosphamide (TAC) chemotherapy followed by chest wall and right axillary irradiation. She then was started on adjuvant endocrine therapy with exemestane and completed 5 years of therapy.
Three years later, she presented to the oncology clinic for a surveillance visit with complaints of chronic dry cough for 2 months, new onset shortness of breath with exertion, and recent unexplained weight loss of 12 lbs. CT imaging was ordered, which revealed right pleural effusion, sub-centimeter pulmonary nodules, pleural thickening, and hilar adenopathy. Thoracentesis with cytology was highly suspicious for malignancy but with inconclusive staining. Pleural biopsy revealed metastatic mammary carcinoma, ER 95%, PR negative, HER2 IHC 2+, FISH non-amplified.
After 18 months on her first-line therapy with letrozole and ribociclib, scans revealed progression of disease with new osseous and liver metastasis. A liquid biopsy was sent and revealed PIK3CA mutation, TMB-2, and microsatellite stability.
You sit down with A.M. to discuss goals of care and options for second-line treatment. She has a high level of health literacy, so you spend some time reviewing multiple options based on adverse event profile, administration, and efficacy data. You explain that she has an actionable mutation on next-generation sequencing testing. The conversation is focused on a combination therapy approach with a PI3K or AKT inhibitor combined with fulvestrant. You explain that the clinical trials SOLAR-1 (alpelisib + fulvestrant vs fulvestrant + placebo) and CAPItello-291 (capivasertib + fulvestrant vs fulvestrant + placebo) both showed higher efficacy in the combination arms than with single-agent fulvestrant, concluding that combination therapy is a superior approach.1,2
You go on to discuss potential adverse events with both alpelisib and capivasertib including hyperglycemia, diarrhea, and rash. She is an insulin-dependent diabetic and recalls difficulty controlling her glucose levels while on intermittent corticosteroids during adjuvant chemotherapy. Her greatest concern is losing control of her diabetes again. Her latest hemoglobin A1C test was 5.5%, so her diabetes is currently well controlled. You tell her that from your own experience, and from trial data, capivasertib comes with a much lower risk of hyperglycemia than alpelisib (63% hyperglycemia in SOLAR-1 vs 16% in CAPItello-291).1,2 She is interested in trying capivasertib plus fulvestrant. She feels confident she can adhere to the prescribed dosing regimen of 4 days on/5 days off with monthly fulvestrant injections and is excited to have an actionable mutation that allows her to receive a combination regimen with higher efficacy than monotherapy. She is hoping diarrhea doesn’t interfere too much with her busy lifestyle but feels this is worth the trade off to avoid hyperglycemia.
She goes on to begin second-line endocrine therapy with capivasertib plus fulvestrant. She tolerates capivasertib well with one dose reduction for diarrhea and ongoing use of loperamide as needed. She does initiate more frequent office visits with her endocrinologist with a mild increase in insulin requirements, but overall, her glucose is still well controlled. A.M. continues on therapy with capivasertib plus fulvestrant.
References
- André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940.
- Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388:2058-2070.
Dose Adjustments and Oral Adherence in a Patient on Capivasertib
Clinical Pearl: If symptom management is optimized but a grade 2 or higher adverse event persists, then dose holds and reductions are often the next best step in managing adverse events and optimizing quality of life in patients with HR-positive metastatic breast cancer. It is important to educate the patient on proper dose timing to maintain oral adherence since many of these regimens often have unique dosing schedules.
L.M. is an 80-year-old female with metastatic HR-positive breast cancer. She was diagnosed at age 61 after a right lumpectomy revealed a 1.4-cm invasive micropapillary carcinoma with lobular features, grade 2, with 1/3 positive sentinel nodes. She received adjuvant TAC chemotherapy for six cycles, then took adjuvant anastrozole for 5 years. Four years after discontinuing her aromatase inhibitor, she presents for a surveillance visit with new bone pain to her lower back and pelvis. Bone scan revealed diffuse osseous metastasis. She was started on first-line treatment of letrozole plus palbociclib. She had a very durable response, so restaging scans were spaced out to every 4 months after 3 years on therapy. Six years after initiating aromatase inhibition with CDK4/6 inhibition, a CT scan revealed new liver metastasis. Next-generation sequencing testing on tissue revealed CDH1, ESR1, CCDN1, FGF3, and AKT1 alterations. After an extensive shared decision-making conversation with her cancer care team about endocrine and targeted therapy options, she decided to pursue elacestrant second line. She had another fairly durable response of 13 months on this treatment. Scans showed some increase in her liver metastases and new abdominal adenopathy. She remained endocrine sensitive based on prior treatment responses, so she was then transitioned to third-line endocrine therapy with capivasertib plus fulvestrant.
Since L.M. has been on once-daily elacestrant for over a year, you take extra time in your visit reviewing the new dosing schedule for capivasertib. She lives with her daughter now since her husband passed several years ago, but she still drives herself to appointments and is able to manage her care fairly well. She admits that in the past if she experienced fatigue, weakness, or other adverse events from therapy, she might occasionally miss or forget doses of her oral endocrine therapy. You get her daughter on the phone to review dosing schedule and the three of you collectively formulate a plan to manage her capivasertib doses with a dosing diary and calendar that they will keep on the refrigerator. They understand that this will be twice-daily dosing (two 200-mg tablets) 4 days on followed by 3 days off weekly.1
Additionally, the patient will come in for monthly fulvestrant injections and lab work with an additional visit on day 15 for fulvestrant and lab monitoring in the first cycle.
L.M. returns to the clinic on day 15 reporting several days of diarrhea up to 6 episodes per day despite proper use of loperamide. You add diphenoxylate/atropine and advise her to alternate this with loperamide with each episode of stool with a 24-hour max of 8 tablets per day. You decide to have her carry on her normal dosing with capivasertib for a week to see if the diphenoxylate/atropine manages this more effectively, advising the patient to have a low threshold to call the clinic if diarrhea is not improving after 24 to 48 hours. On evaluation of her labs, potassium is a bit low at 3.2 mmol/L and creatinine is slightly elevated above her baseline at 1.14 mg/dL. She receives 1000 mL normal saline infusion and 20 mEq intravenous potassium chloride in clinic in addition to her planned fulvestrant injection. You call to check in on her 2 days later and her diarrhea has improved some but she is still having up to 4 episodes per day. You advise her to hold her capivasertib and set an appointment for her to return next week for re-evaluation. She has also been encouraged to increase fluid intake at home this week. You explain that you will pre-emptively send a new dose to her specialty pharmacy for 160-mg tablets so she can resume at a dose reduction when diarrhea improves to no more than 3 episodes per day.
Table: Recommended Dose Modifications of Capivasertib for Diarrhea Adverse Event1
| Severity* | Capivasertib Dosage Modification |
|---|---|
| Grade 2 | Withhold capivasertib until recovery to grade ≤1. If recovery occurs in ≤28 days, resume capivasertib at same dose or one dose lower as clinically indicated. If recovery occurs in >28 days, resume at one dose lower as clinically indicated. For recurrence, reduce capivasertib by one dose lower. |
| Grade 3 | Withhold capivasertib until recovery to grade ≤1. If recovery occurs in ≤28 days, resume capivasertib at same dose or one dose lower as clinically indicated. If recovery occurs in >28 days, permanently discontinue capivasertib. |
| Grade 4 | Permanently discontinue capivasertib. |
*Per CTCAE v5.0 grading for diarrhea.2
When L.M. returns the following week, she no longer needs her loperamide or diphenoxylate/atropine and reports 1 to 2 soft stools per day, but no further watery stools. You again get her daughter on the phone to review the new dosing plan with two 160-mg tablets (total 320 mg) twice daily, 4 days on and 3 days off.1
She returns for her second cycle day 1 fulvestrant injection and scheduled visit the following week and is tolerating this dose much better with occasional use of loperamide and 1 to 2 episodes of diarrhea a few days out of the week. Labs are all within normal limits so you re-educate the patient to call with worsening of more than 3 stools per day and advise her to schedule regularly monthly visits for labs, exam, and fulvestrant injections. L.M. continues her capivasertib/fulvestrant with stable disease with ongoing, intermittent mild diarrhea, mild fatigue, and the occasional episode of nausea.
References
- AstraZeneca. (2011). Truqap (capivasertib) package insert.
- Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. National Cancer Institute Division of Cancer Treatment & Diagnosis. https://dctd.cancer.gov/research/ctep-trials/for-sites/adverse-events/ctcae-v5-5x7.pdf. November 27, 2017. Accessed October 28, 2025.
Proactive Adverse Event Management With Capivasertib and Fulvestrant
Clinical Pearl: Early recognition and intervention, and at times prophylaxis, can be key to more effectively managing adverse events in patients on capivasertib plus fulvestrant for HR-positive metastatic breast cancer.
T.H. is a 48-year-old female with HR-positive metastatic breast cancer. After initial diagnosis revealed a large mass on MRI, she went on to have bilateral mastectomies with pathology showing a 6-cm invasive ductal carcinoma in her right breast, ER 95%, PR 95% HER2 IHC 1+, 0/3 positive sentinel nodes. Her oncotype score was 16 so she did not pursue adjuvant chemotherapy. Germline BRCA testing was negative. She was premenopausal at the time and with node-negative status, she did not feel compelled to pursue aromatase inhibition with ovarian suppression, so went on to take tamoxifen for 5 years. Two years after completing her tamoxifen, she came in with reported palpable axillary adenopathy. Ultrasound revealed multiple masses in her right axilla. Left axilla biopsy is positive for invasive mammary carcinoma, ER 100%, PR 98%, HER2 IHC 0. Work-up with PET scan shows multiple osseous metastases in addition to right axillary uptake. She was initiated on first-line treatment of letrozole plus ribociclib with goserelin for ovarian suppression and denosumab. CT scan after 3 years on first-line treatment revealed progressive disease with multiple new bone metastases and new pulmonary nodules. Liquid biopsy testing revealed ESR1, PIK3CA, AKT1, FGFR1 amplification, EGFR1 amplification, and microsatellite stability.
You sit down with the patient to educate her on adverse event management after the decision is made to pursue capivasertib plus fulvestrant for second-line treatment due to multiple mutations (PIK3CA and AKT1) found on next-generation sequencing that suggest her cancer is signaling through the AKT pathway.
You discuss the risk of diarrhea, rash, and hyperglycemia with capivasertib. She works full time still and has teenage kids with multiple activities each week, so wants to maximize symptom management early on in any way possible.
The risk of cutaneous adverse events, such as rash, is reviewed as 56% of patients in CAPItello-291 had rash of any grade, and 15% of those had grade 3/4 events.1,2 She will plan to take a prophylactic antihistamine, such as daily loratadine, during her first 8 weeks of treatment. We also discuss lifestyle changes to protect the skin, such as using sunscreen daily to sun-exposed areas and fragrance-free soaps/detergents, as well as avoiding topical retinoids, alcohol-based products, and salicylic acid that can be drying to the skin.
You explain that the majority of patients do experience diarrhea, but you do not recommend primary prophylaxis for diarrhea as she already struggles with opioid-induced constipation. She does plan to pick up loperamide to have on hand and take at the first signs of diarrhea.
You tell her that although hyperglycemia can occur on capivasertib, it was only seen in 19% of patients on CAPItello-291,1 but you are concerned she is higher risk as her non-fasting glucose tends to trend in the pre-diabetic range at around 115 to 125 mg/dL and her body mass index is 28. You discuss lifestyle changes such as diet modification to limit carbs and sugar and increased physical activity. You add a hemoglobin A1C test to her baseline labs. Labs come back later in the day that show her hemoglobin A1C at 6.1%. You call her and discuss a referral to endocrinology to optimize her glucose levels, as she is already at risk for diabetes, so that she will have established care if hyperglycemia occurs on treatment.
T.H. receives her capivasertib from her specialty pharmacy and comes in as scheduled for cycle 1 day 1 fulvestrant and then at day 15 for her glucose check and repeat fulvestrant injection. On cycle 2 day 1, you see her for a provider exam and she reports mild fatigue and looser stool than usual but no diarrhea or rash. Labs show a fasting glucose level of 160 mg/dL. You initiate metformin extended release 1000-mg daily, but caution her that metformin can contribute to diarrhea, noting though that the extended-release version generally causes less diarrhea than the immediate release. She is scheduled for an initial consult with her new endocrinologist the following week as well. You review the consult note from the endocrinologist the following week and her fasting glucose level has improved to baseline at 110 mg/dL. You call the patient to check in and she was given glucose testing supplies and is checking it once daily with good control. She will see the endocrinologist every 3 months or as needed for optimal glucose management. She denies any worsening diarrhea.
T.H. goes on to receive a durable benefit from her combination therapy with 11 months on treatment before scans revealed disease progression. She developed a grade 1 maculopapular rash on her chest in cycle 3 after discontinuing her antihistamine. You promptly treated this with a topical corticosteroid three times a day and restarted her loratadine and the rash resolved. She did not need to hold treatment since this covered less than 10% of her body surface area. She continued her antihistamine throughout the remainder of her time on treatment. Her glucose levels returned to baseline after discontinuation of therapy, but she continued to see her endocrinologist bi-annually for hemoglobin A1C monitoring and for accountability visits to discuss positive lifestyle changes.
References
- Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388:2058-2070.
- Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. National Cancer Institute Division of Cancer Treatment & Diagnosis. https://dctd.cancer.gov/research/ctep-trials/for-sites/adverse-events/ctcae-v5-5x7.pdf. November 27, 2017. Accessed October 28, 2025.
Meet the Faculty
Melissa Rikal
FNP-BC, AOCNP
Nurse Practitioner
Sarah Cannon Research Institute
Melissa Rikal, FNP-BC, AOCNP, is a nurse practitioner at Sarah Cannon Research Institute. She specializes in breast cancer and early phase drug development. She is accredited as an advanced oncology certified nurse practitioner through OCN. She has worked in the field of oncology since 2010 and is passionate about providing patient centered care that is research focused. In her free time, Melissa enjoys time with her family, traveling, hiking and anything outdoors!
Let us know what you'd like to learn more about at jadpro-editor@broadcastmed.com