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Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023
| Contributor Information
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Image from Subbiah V, Chuang HH, Gambhire D, Kairemo K. Diagnostics (Basel). 2017;7(1). [Open access.] PMID: 28212290, PMCID: PMC5373019.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Metastatic breast cancer, also known as stage IV or advanced breast cancer, refers to spread of the disease via the lymph nodes or blood to distant sites, such as the bones, lungs, liver, brain, or skin.[1] This condition is incurable, and the 5-year survival for these patients is 31%.[2]
Symptoms/signs of metastatic spread include the following[1,3]:
Dyspnea
Bone pain
Abdominal distention
Jaundice
Localizing neurologic signs
Altered cognitive function
Unexplained weight loss
Hypercalcemia
Increasing levels of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin
New, or increasing size of a preexisting, radiographic anomaly
New abnormal regions noted on functional imaging (eg, bone scan, positron emission tomography/computed tomography [PET/CT] scan)
Assessment of the tumor's estrogen receptor (ER), progesterone receptor (PR), and HER2 status is essential, given the availability of newer treatments for HER2-positive tumors and of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for ER/PR-positive, HER2-negative metastatic breast cancer.
The images shown are pre- and post-fluorodeoxyglucose (FDG) PET scans in a middle-aged woman with metastatic breast cancer and multiple osseous metastases, at baseline (BL) and again at 6 weeks (wk), 4 months (mo), and 10 months after initiation of treatment. At 10 months, new focal sites of activity appeared but without anatomic abnormality. CT = computed tomography; MIP = maximum intensity projection.
Image courtesy of Winston W Tan, MD.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Case 1
A 58-year-old cardiac nurse has a history of a 1.2-cm T1c, N0, M0, ER/PR-positive, HER2-positive (3+ by immunohistochemistry [IHC]) ductal carcinoma. She declined trastuzumab (owing to fear of congestive heart failure) but received 4 cycles of doxorubicin and cyclophosphamide, underwent breast reconstruction, and then received tamoxifen for 10 years.
She presents for her scheduled follow-up. Her laboratory studies reveal a normal complete blood cell (CBC) count and CEA level, but elevated levels of cholesterol, thyroid-stimulating hormone, and AST (64 IU/L).
Her abdominal CT scan is shown. What is the next step in the management of this patient?
Obtain next-generation sequencing
Biopsy the liver
Treat with chemotherapy
Treat with trastuzumab
Image courtesy of Winston W Tan, MD.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Answer: B. Biopsy the liver.
Liver masses identified on abdominal imaging studies have an extensive differential diagnosis, ranging from benign asymptomatic lesions to malignant neoplasms. Obtaining a biopsy specimen from the liver with pathological analysis helps to determine the final diagnosis.[4]
Biopsy shows that the patient's liver lesions are ER/PR-positive, HER2-positive adenocarcinoma, consistent with breast cancer.
Which of the following is the best regimen for management of this patient?
Paclitaxel and trastuzumab
Pertuzumab and trastuzumab
Pertuzumab, trastuzumab, and docetaxel
Ado-trastuzumab and paclitaxel
Image courtesy of Winston W Tan, MD.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Answer: C. Pertuzumab, trastuzumab, and docetaxel
Management of HER2-positive metastatic breast cancer
About 20-25% of breast cancers are HER2-receptor positive.[1] HER2-directed treatments improve survival even in the metastatic setting.[1,5] First-line therapies for treatment-naive patients include monoclonal antibody therapy (trastuzumab, pertuzumab, ado-trastuzumab [TDM1, trastuzumab emtansine]) and/or tyrosine kinase inhibitor therapy (lapatinib) and/or chemotherapy with a taxane.[1,5,6] The American Society of Clinical Oncology (ASCO) recommends trastuzumab, pertuzumab, plus a taxane (eg, docetaxel, paclitaxel) for first-line treatment.[7]
Pertuzumab/trastuzumab/taxane therapy improves clinical outcomes compared with trastuzumab plus docetaxel.[5] This was demonstrated in a phase III trial of 808 women with HER2-positive metastatic breast cancer who were treated with trastuzumab (8 mg/kg intravenous [IV] loading dose, then 6 mg/kg) and docetaxel (75 mg/m2 IV), and then randomly assigned to treatment with pertuzumab (840 mg loading dose, then 420 mg) or placebo.[8] The results—longer progression-free survival (PFS) and overall survival (OS) with the addition of pertuzumab—are shown above.
Adapted images from MedPix | ENS Scott Liu, Russell A Patterson, Uniformed Services University.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
On follow-up, restaging CT scanning shows three new low-attenuation nodules in the right lobe of the liver (top row; bottom row, left image) suspicious for metastatic disease, as well as several new mixed lytic and sclerotic bony metastatic lesions (not shown). (Bottom right image: Well-defined lucencies in the right iliac bone in proximity to the sacroiliac joint.) No worrisome pulmonary nodules and no lymphadenopathy are noted.
The next step in the management of this case should involve discontinuing the current treatment and initiating which of the following treatments?
Lapatinib/capecitabine
Ado-trastuzumab
Pertuzumab/trastuzumab
Any of the above
None of the above
Image from MedPix | ENS Scott Liu, Russell A Patterson, Uniformed Services University.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Answer: B. Ado-trastuzumab[5,9-12]
ASCO recommends ado-trastuzumab (trastuzumab emtansine, T-DM1) for second-line therapy of HER2-positive metastatic breast cancer.[7] For third-line treatment, other HER2-targeted therapy combinations or T-DM1 (if not previously administered) should be offered, and pertuzumab may be offered if not previously given.[7]
Note that the trials supporting second-line use of T-DMI in this setting (EMILIA and TH3RESA) were performed before pertuzumab entered first-line use. However, in observational studies, T-DM1 has shown activity in patients previously treated with pertuzumab.[8] Second, although no predictive biomarker has yet been validated, high levels of HER2 protein or ERBB2 mRNA expression, or lack of HER2 intratumor heterogeneity, might help better select patients for T-DM1.[9] Third, possible first-line use of T-DMI is supported by the phase III MARIANNE trial, which showed noninferior—but not superior—PFS with T-DM1 (with or without pertuzumab) compared with trastuzumab plus a taxane.[10]
Finally, pertuzumab has been shown to be active beyond the first-line setting; the combination of pertuzumab/trastuzumab with or without a cytotoxic agent (eg, vinorelbine or a taxane) may be considered for those with disease progression following trastuzumab-based therapy without pertuzumab.[5,7,12,13]
In addition to her chemotherapy/targeted treatment, which of the following adjuvant therapies would you offer the patient for the bone metastasis?
Calcium and vitamin D
Alendronate
Zoledronic acid
Denosumab
A, C, and D
Anteroposterior pelvic radiograph is from a patient with breast cancer metastasis to the proximal femur and the acetabulum.Image from Guzik G. J Orthop Surg Res. 2016;11(1):54. [Open access.] PMID: 27125184, PMCID: PMC4848795.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Answer: E. A, C, and D
For patients with bone metastasis from breast cancer, denosumab and zoledronic acid have each been shown to reduce skeletal related events (SREs) (but appear to have no impact on OS).[5] International practice guideline groups have not expressed a preference for either agent in the setting of metastatic breast cancer. However, although monthly denosumab may appear preferable to monthly zoledronic acid in terms of its modest SRE reduction, analgesic effects, and subcutaneous route of administration, those benefits of denosumab need to be balanced with its increased direct drug costs.
Bisphosphonates should be used with calcium and vitamin D supplementation.[5]
Image courtesy of Winston W Tan, MD.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Case 2
A 65-year-old woman with a negative family history of cancer presented with shortness of breath and a palpable breast mass.
Biopsy and pathological analysis of the breast mass revealed a 3.5-cm carcinoma that had no necrosis and was ER positive and HER2 negative (1+ by IHC).
Her pulmonary CT scan is shown. Pleural fluid examination was consistent with breast adenocarcinoma with metastasis to the pleura. PET scanning revealed no evidence of metastasis in other body sites.
This patient was treated with paclitaxel for 4 months. She had significant toxicity with treatment, including grade 2 neuropathy.
The next step in management of this case should be initiation of which of the following?
An aromatase inhibitor
Tamoxifen
Fulvestrant
Letrozole and palbociclib
Metastatic breast cancer cells in pleural fluid. Image from flickr, Ed Uthman.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Answer: D. Letrozole and palbociclib
In a phase III study that included 666 postmenopausal patients with metastatic ER-positive, HER2-negative breast cancer who had not had prior treatment for advanced disease, the combination of palbociclib and letrozole demonstrated improved PFS of 24.8 versus 14.5 months (hazard ratio [HR] 0.58, 95% CI 0.46-0.72) and objective response rate (ORR) of 42% versus 35%, compared with letrozole alone.[14,15]
Image courtesy of Winston W Tan, MD.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Case 3
A 48-year-old woman presents with new-onset back pain. She states she was diagnosed with breast cancer 13 years ago, underwent mastectomy, and received chemotherapy for approximately 8-9 months. One of the drugs may have been 5-fluorouracil (5-FU). She also took tamoxifen for approximately 11 years.
Imaging is performed. Which of the following does the image show?
Metastasis to the thoracic spine
Metastasis to the intestines
Metastasis to the liver
Metastasis to the lungs
Image courtesy of Winston W Tan, MD.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Answer: A. Metastasis to the thoracic spine (The arrow indicates bone metastasis at T10.)
MRI of the thoracic spine demonstrates multifocal metastatic disease, and a PET scan reveals widespread osseous metastatic disease. There is no evidence of involvement of the lymph nodes, liver, or lungs. She receives palliative radiotherapy to the spine with significant improvement in her back pain. Biopsy of several lesions show HER2-negative, ER-positive disease. She refuses tamoxifen and instead receives a course of exemestane (estrogen modulator) and anastrozole (aromatase inhibitor); 6 months later, letrozole (aromatase inhibitor) is initiated because of arthralgia. She also receives monthly denosumab.
The following year, her imaging scans show disease progression with new metastases to the sacrum and ribs. Which of the following would be her best treatment option?
Fulvestrant
Fulvestrant and palbociclib
Capecitabine
Eribulin
All of the above
Abdominopelvic CT scan in an elderly patient with ER positive, HER2 negative recurrent breast cancer and metastasis to the urinary bladder reveals hydronephrosis (white arrow) and bladder wall thickening (yellow arrow) (bladder catheter in situ). Image from Nieder C, Pawinski A. Case Rep Oncol Med. 2014;2014:931546. [Open access.] PMID: 24716053, PMCID: PMC3970251.
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Answer: B. Fulvestrant and palbociclib
Although all of the options are appropriate, hormonally-targeted treatment is less toxic than chemotherapy, and combination therapy with an estrogen blocker would further improve survival in this patient. Fulvestrant/palbociclib has been shown to improve PFS in hormone-receptor (HR)–positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy.[5,16,17]
For most patients with HR-positive disease, it is preferable to start with estrogen antagonist treatment (ET), reserving chemotherapy for patients whose cancers appear to be refractory to ET or who have extensive symptomatic visceral involvement. The addition of targeted therapies to ET may improve PFS, although OS results remain pending.[16,17] Agents used for such targeted therapies include everolimus or CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib). In patients with HR-positive, HER2-negative breast cancer that has PIK3CA mutations, fulvestrant plus the PI3K inhibitor alpelisib has been shown to improve PFS.[18]
Image identifying a palliative approach in the literature from Sawatzky R, Porterfield P, Lee J, et al. BMC Palliat Care. 2016;15:5. [Open access.] PMID: 26772180, PMCID: PMC471527
Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care
Winston W Tan, MD; Matthew Tan, BS Biomedical Science | May 25, 2023 | Contributor Information
Palliative Care
Treatment of metastatic disease is palliative, with "the goal to anticipate, prevent, and reduce suffering," as well as to improve quality of life.[19,20] A study in patients with metastatic non–small-cell lung cancer found that those who received early palliative care not only experienced significant improvements in quality of life and mood but also had longer survival, with less aggressive care at the end of life.[21]
Referral for palliative care should be made at the time of diagnosis of metastasis. This can lead to better patient care.[21]
ASCO recommends considering the combination of palliative care with standard oncology care early in the treatment course for patients with metastatic cancer and/or a high symptom burden. Specific recommendations are as follows[20]:
The time to start palliative care is as soon as a patient's cancer becomes advanced.
For newly diagnosed patients with advanced cancer, consider early palliative care involvement within 8 weeks after diagnosis.
Inpatients and outpatients with advanced cancer should receive dedicated palliative care services early in the disease course concurrent with active treatment.
Essential components of palliative care may include the following[19]:
Building rapport and relationships with patients and family caregivers (eg, cultural sensitivity, acknowledging patients' wishes)
Managing symptoms, distress, and functional status
Exploration of understanding and education about the illness and prognosis
Clarification of treatment goals
Assessment and support of coping needs (eg, provision of dignity therapy)
Assistance with medical decision making
Coordination with other care providers
Provision of referrals to other care providers as indicated
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Contributor Information
Winston W Tan, MD
Professor of Medicine
Mayo Clinic
Jacksonville, Florida
Disclosure: Winston W Tan, MD, has disclosed no relevant financial relationships.
Matthew Tan, BS, Biomedical Science
Disclosure: Matthew Tan, BS Biomedical Science, has disclosed no relevant financial relationships.
National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. Cancer stat facts: female breast cancer. Available at: https://seer.cancer.gov/statfacts/html/breast.html. Accessed May 10, 2023.
Rodriguez de Lope C, Reig ME, Darnell A, Forner A. Approach of the patient with a liver mass. Frontline Gastroenterol. 2012 Oct;3(4):252-62. PMID: 28839677
National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology (NCCN guidelines): Breast Cancer. Version 4.2023 — March 23, 2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 10, 2023.
Giordano SH, Temin S, Davidson NE. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO clinical practice guideline update summary. J Oncol Pract. 2018 Aug;14(8):501-4. PMID: 29989839
Conte B, et al; Gruppo Italiano Mammella (GIM) study group: T-DM1 efficacy in patients with HER2-positive metastatic breast cancer progressing after a taxane plus pertuzumab and trastuzumab: An Italian Multicenter Observational Study. Clin Breast Cancer. 20:e181-e187, 2020. PMID: 31735691
Griguolo G, Brasó-Maristany F, González-Farré B, et al: ERBB2 mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer. Cancers (Basel). 12:1902, 2020. PMID: 32674482
Perez EA, Barrios C, Eiermann W, et al: Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: Primary results from the phase III MARIANNE study. J Clin Oncol 35:141-148, 2017. PMID: 28056202
Swain SM, Baselga J, Kim SB, et al, for the CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. PMID: 25693012
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Cardoso F, Paluch-Shimon S, Sekus E, et al: 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC5) Ann Oncol. 2020:31;1623-1649. PMID: 32979513
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Turner NC, Ro J, Andre .F, et al, for the PALOMA3 Study Group. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. PMID: 26030518
Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-39. PMID: 26947331
André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021 Feb;32(2):208-217. PMID: 33246021
Ferrell BR, Temel JS, Temin S, et al. Integration of palliative care into standard oncology care: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017 Jan;35(1):96-112. PMID: 28034065
Temel JS, Greer JA, Muzikansky A et al. Early palliative care for patients with metastatic non–small-cell lung cancer. N Engl J Med. 2010 Aug 19;363(8):733-42. PMID: 20818875
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