Case study 83.1

Brain Metastases

A 35-year-old African American woman presented with a 5 cm mass in the right breast. Biopsy revealed high-grade triple-negative invasive ductal carcinoma. There were multiple lung and liver metastases documented on positron emission tomography (PET) scan. She was BRCA negative.

She was treated with six cycles of taxotere, adriamycin, and cytoxan and achieved a complete remission clinically and radiologically, and was then maintained for an additional six cycles of taxotere and cytoxan. Approximately 12 months after starting chemotherapy, she developed severe headaches. Magnetic resonance imaging (MRI) showed a single 2 cm mass in the right frontal cortex. Computed tomography (CT) scans revealed no evidence of liver and lung metastases.

1. How would you treat her?

Recommend surgical resection
Surgical resection followed by radiation
Radiation therapy (whole-brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS))
Intrathecal methotrexate

Approximately 10–15% of patients with metastatic breast cancer will develop clinical evidence of central nervous system (CNS) recurrence, usually late in the course of the disease. The incidence appears to have increased in recent years, because of better control of systemic disease resulting in a higher incidence of metastases in sanctuary sites such as the CNS.

Brain metastases are most commonly seen in patients with biologically aggressive breast cancer, particularly triple-negative or Her2neu-positive disease. Several studies of patients with Her2-positive metastatic breast cancer treated with trastuzumab-based regimens have reported an incidence of CNS metastases ranging from 28% to 43%.

Median time to brain metastases was shorter for estrogen receptor (ER)-negative and HER2-positive compared with ER-positive disease. Over one-half of the patients who develop CNS metastases do so when their systemic disease was stable or responding to systemic treatment.

Treatment of CNS metastases is generally irradiation and surgery. Although most patients have multiple metastases, patients with a single resectable metastasis should be referred for surgery, as the median survival of such patients is significantly longer.

Several radiation techniques have been used; these include WBRT and SRS.

The place of drug treatment following radiation therapy is limited in most patients; because of the blood–brain barrier, few chemotherapy drugs attain high levels in the CNS. One exception is the small-molecule tyrosine kinase inhibitor lapatinib, which has shown modest efficacy in Her2-positive brain metastases. Current research attempts are focused on methods to disrupt the blood–brain barrier and increase chemotherapy penetration of the CNS. Herceptin can be given intrathecally where indicated.

Prognosis is best in patients <50 years of age, with good performance status, good control of systemic disease, and ER- or Her2-positive disease, and in patients who have surgical resection of CNS disease.

In this case, where there was an isolated brain metastasis in a surgically resectable area, an aggressive approach was warranted.

Case study 83.2

“Adjuvant” Therapy of Locally Recurrent Disease after Resection

A 60-year-old woman presented with several subcentimeter nodules in the left mastectomy scar, 7 years after mastectomy, adjuvant chemotherapy (AC; four cycles of AC followed by four cycles of Taxol), and radiation, and 5 years of adjuvant anastrazole for a T2N1M0 ER- and PR-positive invasive ductal carcinoma. Metastatic evaluation revealed no evident nodal, visceral, or bone metastases.

The recurrent tumor was surgically excised. Pathology was consistent with the original tumor.

1. What treatment would you recommend?

Restart aromatase inhibitor
Observation only
Radiation
Course of postresection chemotherapy followed by chemotherapy and endocrine therapy

Overall 10–20% of patients with stage 1–3 breast cancer will develop a loco-regional recurrence during the first 10 years after diagnosis. Most of these patients will have local chest wall or axillary recurrence without systemic metastases.

Surgical resection and radiation (if feasible) are the initial treatment of choice for such patients. Second local recurrences are seen in 60–70% of patients treated by surgical excision alone.

Re-irradiation following postmastectomy radiation carries an unacceptable risk of toxicity.

Until recently, there were only limited data to support the use of systemic treatment after surgical removal of locally recurrent disease. A randomized Swiss study published in 2003 demonstrated increased recurrence-free survival when tamoxifen was compared with observation after surgery.

The CALOR study, reported at the 2012 San Antonio Breast Cancer Symposium, demonstrated significant reduction in both 5-year disease-free and overall survival. These results were seen in patients with both ER-positive and ER-negative disease.

Case study 83.3

How to Choose Appropriate Systemic Therapy for the Patient with Newly Diagnosed Metastatic Disease

Two years after lumpectomy and radiation therapy for a T1N1M0 ER-positive, PR-positive, and Her2-negative cancer of the left breast, a 45-year-old woman presented with abdominal bloating. Following her original surgery she had declined adjuvant chemotherapy and endocrine therapy, but received postlumpectomy radiation. She is known to be BRCA negative.

CT scan showed numerous liver lesions. Remainder of metastatic evaluation was negative. Biopsy of liver confirmed the clinical diagnosis of metastatic ER-positive breast cancer.

1. Which would be the best choice of treatment for this patient? (Choose all that apply.)

Endocrine therapy
Single-agent chemotherapy
Combination chemotherapy
Entry on a clinical trial

The goals of treatment for a patient with metastatic disease are to provide palliation, improve quality of life, and prolong survival.

Treatment options include combination and sequential single-agent chemotherapy. Additionally, in patients with ER-positive disease, there are numerous options for endocrine therapy, and there are also now available several drugs that target the Her2 pathway in patients with Her2-positive disease.

What factors help the oncologist decide which treatment is most appropriate? Broadly speaking, the most important factors are the biology of the tumor and relevant prognostic factors, which include disease-free interval, sites of metastatic disease (visceral vs. nonvisceral sites), prior (adjuvant) systemic therapy, and extent of organ dysfunction and comorbidities.

Endocrine Therapy versus Chemotherapy

In general, endocrine therapy is usually the first option for most women with metastatic ER-positive disease. Endocrine therapy, designed to minimize estrogen stimulation of the tumor, is less toxic than chemotherapy and often produces responses of long duration.

This patient has received no prior therapy, and has a high probability of response to whatever drug treatment is used. She does have numerous liver lesions, however, and this represents a life-threatening clinical scenario. Median duration of survival for the patient with liver metastases who does not achieve clinical remission is generally less than 12 months. Endocrine therapy would therefore not be recommended as initial treatment here.

Single-Agent Chemotherapy versus Combination Chemotherapy

In general, combination chemotherapy produces higher overall response rates, longer time to progression, and longer overall survival when compared with single-agent chemotherapy, at a cost of higher toxicity.

Sequential single-agent chemotherapy is generally used in patients with less dire clinical scenarios, where there may be a longer disease-free interval from initial treatment until first recurrence, a lesser body burden of metastatic disease, and an absence of disease in dire visceral sites (liver, lymphangitic lung, and CNS).

This patient has several poor prognostic factors, which include the relatively short disease-free interval and, most importantly, the presence of numerous liver metastases, which are symptomatic.

In such a clinical scenario, the use of aggressive combination chemotherapy would be most appropriate. Given the fact that she is chemotherapy naïve, there is a high probability (approximately 60%) that combination chemotherapy would achieve a partial remission with a relatively low probability of complete remission (approximately 20%).

Most patients can expect relief of symptoms from shrinkage of the liver metastases. In general, remissions from any one treatment regimen tend to be of relatively short duration (median length approximately 9 months). Second remissions from subsequent treatment are common, however.

There are a large number of agents active against metastatic breast cancer. Most physicians would choose first-line treatment with an anthracycline- or taxane-containing regimen, which have shown an overall survival benefit in randomized studies.

The patient may be offered entry on an appropriate clinical trial if one is available.

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