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Bone scan in 66-year-old woman with metastatic breast carcinoma shows abnormal radionuclide activity from metastases throughout the spine, ribs, sternum, pelvis, hips, and skull.

Metastatic Breast Cancer: A Review of 3 Cases and Palliative Care

Winston W Tan, MD; Matthew Tan, BS Biomedical Science | June 24, 2022 | 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 from beyond the breast to distant sites, such as the bones, lungs, liver, brain, or skin.[1] This condition is incurable, and the 5-year survival for metastatic breast cancer is 29%.[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
  • Rising levels of tumor markers (eg, carcinoembryonic antigen [CEA], CA15-3, CA27.29)
  • New, or increasing size of a preexisting, radiographic anomaly
  • New abnormal regions noted on functional imaging (eg, bone scan, 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.

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 | June 24, 2022 | 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 (Adriamycin) 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, as well as 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?

  1. Obtain next-generation sequencing.
  2. Biopsy the liver.
  3. Treat with chemotherapy.
  4. 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 | June 24, 2022 | 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?

  1. Paclitaxel and trastuzumab
  2. Pertuzumab and trastuzumab
  3. Pertuzumab, trastuzumab, and docetaxel
  4. 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 | June 24, 2022 | 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 and overall survival 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 | June 24, 2022 | 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 patient should involve discontinuing the current treatment and initiating which of the following treatments?

  1. Lapatinib/capecitabine
  2. Ado-trastuzumab
  3. Pertuzumab/trastuzumab
  4. Any of the above
  5. 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 | June 24, 2022 | Contributor Information

  1. Answer: B. Ado-trastuzumab[5,9-12]

ASCO recommends trastuzumab emtansine (ado-trastuzumab, TDM1) for second-line therapy.[7] For third-line treatment, other HER2-targeted therapy combinations or trastuzumab emtansine (if not previously administered) should be offered, and pertuzumab may be offered if not previously given.[7]

The addition of lapatinib to capecitabine is effective for women with HER2-positive, advanced breast cancer progression after treatment with anthracycline-, taxane-, and trastuzumab-based therapy.[9] Similarly, ado-trastuzumab improves overall survival (OS) in this population.[10,11] 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]

Which of the following adjuvant therapy would you offer the patient in addition to her chemotherapy/targeted treatment for the bone metastasis?

  1. Calcium and vitamin D
  2. Alendronate
  3. Zoledronic acid
  4. Denosumab
  5. 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 | June 24, 2022 | 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 | June 24, 2022 | 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?

  1. An aromatase inhibitor
  2. Tamoxifen
  3. Fulvestrant
  4. 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 | June 24, 2022 | 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 progression-free survival (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 | June 24, 2022 | 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?

  1. Metastasis to the thoracic spine
  2. Metastasis to the intestines
  3. Metastasis to the liver
  4. 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 | June 24, 2022 | 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?

  1. Fulvestrant
  2. Fulvestrant and palbociclib
  3. Capecitabine
  4. Eribulin
  5. 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 | June 24, 2022 | 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 | June 24, 2022 | 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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