Oxford Case Histories in Oncology

Case 6

Single brain metastasis from breast cancer

Thankamma Ajithkumar

Case history

A 51-year-old woman presented to the emergency department with a 5-day history of increasing headache and drowsiness. She had had no significant illnesses in the past. All blood tests were normal. She had a CT scan followed by a MRI scan of the brain (Fig. 6.1).

Fig. 6.1

Question

1. What do the CT and MRI scans show in Fig. 6.1?

Answer

1. What do the CT and MRI scans show in Fig. 6.1?

The CT scan shows a well-defined peripheral hyperdense tumour over the left frontal region, which enhances uniformly. It has a broad base along the frontal bone with no evidence of thickening of the underlying bone (hyperostosis). There is surrounding oedema and mass effect with effacement of the lateral ventricle. The MRI scan shows a hypointense well-defined lesion in the frontal region which enhances with no areas of necrosis. There is associated oedema. The differential diagnoses of a well-defined lesion in the brain with contrast enhancement are meningioma, high-grade brain tumour, lymphoma, and metastasis. As meningioma is slow growing, oedema is not a common associated feature (except in the anaplastic variant), so the oedema in this case raises the suspicion of a high-grade brain neoplasm or metastasis.

Subsequently this patient underwent a complete macroscopic excision of the brain lesion. Histology showed a poorly differentiated adenocarcinoma, which on immunohistochemical staining was positive for CK7 and epithelial membrane antigen (EMA), and negative for ER and PgR receptors, CK20, and TTF-1.

Questions

2. How do you interpret the immunohistochemistry?

3. How would you investigate further?

Answers

2. How do you interpret the immunohistochemistry?

Histology shows a poorly differentiated adenocarcinoma. The common primary sites are lung, breast, and the gastrointestinal system. Immunohistochemistry using CK7, CK20, and TTF-1 is useful for identifying the primary tumour. TTF-1 helps to distinguish pulmonary from non-pulmonary adenocarcinoma. TTF-1 is positive in 81% of lung cancers and 69% of metastatic lung cancers. CK20 is not expressed in lung cancer but is positive in gastrointestinal adenocarcinoma and urothelial tumours. CK7 is not expressed in gastrointestinal cancers but is positive in lung, breast, endometrial, and ovarian cancers. A combination of CK7+/CK20– is seen in 100% of lung cancers, 88% of breast cancers, and 87% of ovarian cancers. Table 6.1 shows the various possible combinations of CK7/CK20 staining.

The combination of CK7+, CK20–, and TTF-1- in this case suggests the possibility of lung or breast cancer (the two most common primaries metastasizing to brain). TTF-1 positivity is useful to confirm lung adenocarcinoma, but a negative result cannot rule out a lung primary. Similarly, ER and PgR positivity can only point towards a hormone-positive breast cancer, but ER and PgR negativity cannot rule out a breast cancer.

Table 6.1 Correlation of primary tumours with CK7 and CK20 staining

3. How would you investigate further?

The immunohistochemistry suggests a possible lung or breast cancer with ovarian, pancreatic, or biliary cancer being less likely alternatives. Since there is a possibility of this being a HER-2-positive breast cancer, the HER-2 status needs to be assessed.

The primary tumour site can be established in half of patients presenting with brain metastases from an unknown primary. Hence further radiological staging investigations with CT scan of the chest, abdomen, and pelvis are needed to identify a possible primary tumour. Some studies suggest that there is little value in routine mammography or breast imaging in patients with brain metastases of unknown primary because such a presentation of breast cancer is uncommon.

A CT scan of the chest, abdomen, and pelvis was unremarkable except for a 13mm right axillary lymph node. A mammogram showed a small area of asymmetric increased parenchymal density in the right upper inner quadrant suspicious of a malignancy. This lesion was unchanged compared with a screening mammogram taken 6 months previously. However, an ultrasound guided biopsy from the parenchymal density showed a grade 2 invasive carcinoma staining positive for E-cadherin, HER-2/neu, and GCDFP-15. Meanwhile, the pathologist had reported the brain lesion to be HER-2/neu 3+. The patient subsequently underwent a PET scan which showed uptake in the right axillary lymph node, T11 and L5 vertebrae, and the left sacroiliac joint.

Questions

4. What is the significance of staining with E-cadherin and GCDFP-15?

5. Do you advise any further treatment to the brain?

6. What would be your approach to the management of breast cancer in this woman?

7. If your treatment includes trastuzumab, for how long would you recommend it?

8. How will you assess the response and what would be your follow-up plan?

Answers

4. What is the significance of staining with E-cadherin and GCDFP-15?

E-cadherin distinguishes lobular from ductal carcinoma. A negative E-cadherin stain confirms lobular carcinoma (specificity 97.7%; negative predictive value 96.8%; sensitivity 88.1%; positive predictive value 91.2%) whereas ductal carcinomas invariably stain positive with E-cadherin. GCDFP-15 is a useful marker for identifying metastatic breast cancer in the absence of previous history of breast cancer and/or in tumours which are negative for ER and PgR. It has a specificity of 95% and sensitivity of 74%. Positivity for both these stains hence suggests primary breast cancer (as opposed to metastasis to the breast) of ductal origin.

5. Do you advise any further treatment to the brain?

This patient had a complete macroscopic excision of the brain metastasis. The role of post-operative radiotherapy after complete excision of a tumour is debatable. One randomized trial of 95 patients compared immediate post-operative whole-brain radiotherapy with observation and salvage whole-brain radiotherapy at progression. The study showed improved surgical bed and distant recurrence rates (10 and 18% versus 46 and 70%) with immediate radiotherapy, but without an improvement in OS. However, this study was not powered to detect any improvement in OS (Patchell et al. 1998). A retrospective study of stereotactic radiosurgery to the resection cavity showed an actuarial local control rate of 79% at 1 year (Soltys et al. 2008).

In summary, there is no definite evidence for advocating routine post-operative radiotherapy after complete resection of a solitary metastasis. Nevertheless, many clinicians recommend post-operative whole-brain radiotherapy giving a dose of 25–30Gy in 10–15 fractions.

6. What would be your approach to the management of breast cancer in this woman?

This woman has a histologically proven small-volume metastatic breast cancer with a completely excised brain metastasis. Patients with one to five metastatic lesions usually limited to a single organ are often referred to as having oligometastatic disease. It has been estimated that 1–10% of newly diagnosed oligometastatic breast cancers can be ‘cured’ (Hanrahan 2005) with an aggressive approach involving surgery, radiotherapy, and systemic treatment. Since this patient has metastasis in more than one organ, this case is not one of oligometastatic disease but just low-volume metastatic disease. The clinical challenges in this case are, thus, to decide the optimal systemic therapy (whether trastuzumab alone or in combination with chemotherapy) and its duration, and to define the role of loco-regional therapy.

The options for first-line treatment in this patient include single-agent trastuzumab or a combination of chemotherapy with trastuzumab. The optimal systemic treatment for metastatic breast cancer is not known. The choice is between sequential single agents and combination chemotherapy. In the majority of patients the overall survival with single-agent systemic agents is equivalent to that with combination chemotherapy. The decision regarding the choice of initial treatment depends on various patient-related factors such as menopausal status, ECOG performance status, patient preference, etc., and disease-related factors such as HER-2 status, ER/PgR status, tumour burden, and the need for rapid disease and/or symptom control (Cardoso et al. 2009). For patients in whom speedy disease control is not warranted (i.e. those without life-threatening visceral metastases and/or rapidly progressive disease) sequential single-agent treatment is preferred.

In HER-2-positive patients, a number of studies have shown that the addition of trastuzumab to chemotherapy results in high rates of response and better PFS and overall survival than chemotherapy alone. However, it is not known whether the addition of chemotherapy to trastuzumab improves outcome in HER-2-positive patients compared with trastuzumab alone. The only study of this is a randomized phase II trial comparing trastuzumab plus docetaxel with sequential trastuzumab followed by docetaxel at progression (Hamberg et al. 2011). This small study of 101 patients showed a similar PFS in both arms (9.4 months in the combination arm and 9.9 months in the sequential one). The objective response rate was better with combination therapy (79 vs. 53%, P = 0.016). Overall survival was non-significantly shorter in the sequential arm (30.5 vs. 19.7 months, P = 0.11).

Since this patient has low-volume metastases without life-threatening or rapidly progressive disease, single-agent treatment with trastuzumab is an acceptable choice.

The role of loco-regional treatment in metastatic breast cancer is not known. Retrospective studies suggest that resection of the primary tumour in metastatic breast cancer improves OS and median PFS. This benefit may be attributable to a reduced tumour burden and/or to better accessibility of systemic treatment. However, it cannot be routinely recommended (Pockaj et al. 2010).

7. If your treatment includes trastuzumab, for how long would you recommend it?

The optimal duration of trastuzumab monotherapy in metastatic breast cancer is unknown. Many clinicians prefer to recommend treatment until progression, in the absence of toxicity, or if patient wishes to discontinue.

8. How will you assess the response and what would be your follow-up plan?

Methods for assessing response include clinical examination, imaging, and serial assays of cancer antigen 15-3 (CA15-3) and CEA. However, tumour markers need to be used carefully as levels can rise (‘flare’) during the first 2 months of treatment. Similarly, bone scans may also show a ‘healing flare’ in the initial months which can persist for as long as 12 months. Follow-up should be tailored to the individual clinical needs.

Treatment and follow-up

This patient received whole-brain radiotherapy (30Gy in 10 fractions) followed by 3-weekly trastuzumab as a single agent. Re-staging after 4 years showed no evidence of recurrence or progression of brain disease, and stable disease in other sites. She continues on trastuzumab with no side-effects.

Further reading

Brown PD, Asher AL, Farace E. Adjuvant whole brain radiotherapy: strong emotions decide but rational studies are needed. International Journal of Radiation Oncology Biology Physics 2008; 70: 1305–1309.

Cardoso F, Bedard PL, Winer EP, et al. International guidelines for management of metastatic breast cancer: combination vs sequential single-agent chemotherapy. Journal of the National Cancer Institute 2009; 101: 1174–1181.

Hamberg P, Bos MM, Braun HJ, et al. Randomized phase II study comparing efficacy and safety of combination-therapy trastuzumab and docetaxel vs. sequential therapy of trastuzumab followed by docetaxel alone at progression as first-line chemotherapy in patients with HER2+ metastatic breast cancer: HERTAX trial. Clinical Breast Cancer 2011; 11: 103–113.

Hanrahan EO, Broglio KR, Buzdar AU, et al. Combined-modality treatment for isolated recurrences of breast carcinoma: update on 30 years of experience at the University of Texas M.D. Anderson Cancer Center and assessment of prognostic factors. Cancer 2005; 104: 1158–1171.

Pagani O, Senkus E, Wood W, et al. International guidelines for management of metastatic breast cancer: can metastatic breast cancer be cured? Journal of the National Cancer Institute 2010; 102: 456–463.

Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. Journal of the American Medical Association 1998; 280: 1485–1489.

Pockaj BA, Wasif N, Dueck AC, et al. Metastasectomy and surgical resection of the primary tumor in patients with stage IV breast cancer: time for a second look? Annals of Surgical Oncology 2010; 17: 2419–2426.

Soltys SG, Adler JR, Lipani JD, et al. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases. International Journal of Radiation Oncology Biology Physics 2008; 70: 187–193.