Multiple Hepatic Lesions in a Patient With a History of DCIS

The Case

An asymptomatic 45-year-old woman presented for a screening mammogram and was noted to have a soft-tissue opacity with calcifications in the left breast. Ultrasound revealed a highly suspicious mass that measured 15 × 14 × 15 mm. A core needle biopsy demonstrated poorly differentiated ductal carcinoma in situ (DCIS). Immunohistochemistry (IHC) was positive for estrogen receptor (ER) but negative for progesterone receptor (PR). The patient decided to undergo bilateral mastectomy with breast reconstruction. Pathology further confirmed multifocal DCIS of the left breast without evidence of micrometastasis or invasive ductal carcinoma (IDC). Given the patient’s age at diagnosis and a family history of breast cancer in a first-degree relative (her mother), genetic testing for BRCA1 and BRCA2 mutations was performed; the results were negative.

Seven years later, the patient presented with fatigue, gradual unintended weight loss, right upper quadrant pain, and nausea. She was postmenopausal at this time. Laboratory tests were notable for mild elevation of her alkaline phosphatase, aspartate transaminase, and alanine transaminase levels. Given the abnormal blood tests and symptoms concerning for malignancy, bone scintigraphy and contrast computed tomography (CT) studies were ordered. Bone scintigraphy results were unremarkable, but CT disclosed five hepatic lesions with low attenuation (Figure). Biopsy of a liver lesion confirmed poorly differentiated invasive adenocarcinoma. IHC demonstrated human epidermal growth factor receptor 2 (HER2) and PR negativity, but was positive for pancytokeratin, globin transcription factor 3 (GATA-3), and ER.

1. Based on the preceding clinical scenario, which of these statements is true?

A. Wide excision alone, rather than mastectomy, would have been a more appropriate approach to manage the initial breast mass, given the diagnosis of DCIS and lack of microinvasion on pathology.

B. Breast cancer is the most likely primary source of the liver lesions, given the patient’s clinical history and the histochemical characteristics of the liver lesion biopsy specimen.

C. The hepatic lesions are unlikely to be due to breast cancer, since pathology of the previously resected tumor showed pure DCIS
without evidence of microinvasion or IDC.

D. The primary cancer is likely breast adenocarcinoma, and the
patient should have received 5 years of tamoxifen after her original DCIS diagnosis.

2. Which of these represents the best management option for this patient now?

A. Local therapy consisting of surgical removal of the metastatic lesions, given the oligometastatic nature of her disease.

B. Localized stereotactic body radiation therapy (SBRT), given the oligometastatic nature of disease and the potential complicationsof surgery.

C. Antiendocrine therapy alone or with local therapy (SBRT or surgery).

D. Systemic chemotherapy alone or with local therapy (SBRT or surgery).

Discussion

Standard breast cancer markers (HER2, ER, PR), as well as GATA-3 positivity, are useful histochemical markers used to confirm a diagnosis of breast cancer recurrence or metastasis.[1] Imaging did not demonstrate a new primary malignancy or local recurrence. As a result, this patient’s hepatic lesions were reasonably considered metastatic from a primary adenocarcinoma of the breast (Question 1, Answer B), even though the original tumor stage would have made a metastatic recurrence unlikely.

The management of DCIS can at times pose a dilemma for clinicians, as they must carefully balance the risk of disease recurrence against the potential for overly aggressive treatment. Clinical and pathologic characteristics (eg, palpable mass, larger size, unfavorable histology, and age < 50 years) can help predict the risk of local recurrence but are imperfect prognostic markers. Mastectomy or lumpectomy and adjuvant radiation remain the standard of care.[2] Wide excision alone would not be considered an appropriate approach to management of this patient’s initial breast mass (thus, Answer A is incorrect). Sentinel lymph node biopsy in patients with DCIS is typically performed in those who require mastectomy[3] and often when microinvasion is identified on the initial core biopsy. There are ongoing efforts to individualize therapy and define a low-risk population that would not derive benefit from adjuvant radiation, based on histology[4] or results of multi-gene assays.[5] When ER-positive DCIS is treated with breast-conserving surgery, antiendocrine therapy is encouraged but requires an individualized approach based on risk assessment, given the lack of an overall survival benefit.[6]

Answer C is incorrect because it assumes that lack of microinvasive DCIS is incompatible with later development of metastatic breast cancer. Although the development of metastatic disease following a diagnosis of pure DCIS is extremely rare, it has been previously reported.[7] Distant metastases have been reported in a small number of patients with microinvasive disease[8]; however, microinvasion could be missed during review of multifocal DCIS. In addition, hematogenous spread of breast cancer cells to bone marrow in DCIS without microinvasion has been observed as well.[9] Even though the clinical importance of such findings still needs to be elucidated, they offer a potential mechanism for the development of distant disease.

Answer D is incorrect since antiendocrine therapy is not indicated in DCIS after bilateral mastectomy. Adjuvant tamoxifen would be indicated only in cases of invasive breast cancer or ER-positive DCIS treated with breast-conserving surgery.

In general, the first consideration when approaching a patient with newly diagnosed metastatic breast cancer is whether the patient has oligometastatic or widely metastatic disease. The term “oligometastases” is commonly used to describe metastatic lesions that are confined to a single organ or that are limited in number at the time of presentation. The significance of having oligometastatic disease revolves around the greater potential for long-term progression-free survival after local treatment. This has been seen in patients who have undergone surgical resection for liver metastases from colon primaries or isolated metastases from breast cancer.[10] With respect to localized therapy in our patient, multiple options, including surgery, radiation therapy, and radioembolization, could be considered.

Surgery in patients with oligometastatic liver disease has been shown to be effective. A systematic review of published studies demonstrated that approximately 30% of patients survived 5 years post-resection, and about two-thirds of the patients were disease-free.[10] Not all patients can be treated with surgery, as this may delay initiation of systemic therapy (considered standard of care in this setting), and a surgical approach should thus be considered on an individual basis.[11] Specifically, surgery is contraindicated in those who have diffuse liver metastases, large tumors, or tumor that extends into major blood vessels or other vital structures. Hence, in Question 2, Answer A is incorrect.

Currently, SBRT is commonly used to treat liver metastases, given its ability to limit toxicity to normal tissue. The majority of the studies that have evaluated the use of SBRT in this setting have demonstrated favorable 2-year local control and survival rates, but these studies have been small.[12] One of the larger studies consisted of 47 patients and showed low rates of toxicity, with respectable rates of 2-year local control and survival (92% and 32%, respectively).[13] Even though guidelines for treatment of liver metastases with SBRT have not been established, patients receiving SBRT would ideally have lesions less than 6 cm in size and a maximum of 3 metastatic lesions, with 700 mL of the normal liver receiving less than 15 Gy.[13] Adherence to such constraints has been shown to result in acceptable safety and efficacy; however, further evaluation of the safety of SBRT for metastatic disease is being evaluated in an ongoing phase I study [14]. Nonetheless, SBRT alone is not an appropriate management plan for a patient with metastatic breast cancer (and Answer B thus is incorrect).

Antiendocrine therapy is considered standard-of-care first-line treatment for a patient with metastatic hormone receptor (HR)-positive and HER2-negative breast cancer (Answer C).

Chemotherapy as first-line treatment in patients with metastatic HR-positive breast cancer is indicated in cases of bulky visceral disease or in patients nearing a visceral crisis. In such cases, single-agent therapy or even combination chemotherapy would be warranted in order to achieve a faster response. After the achievement of disease control or development of treatment-related toxicities, a switch to antiendocrine therapy would be warranted. However, since this patient did not have bulky disease or evidence of impending compromise of liver function, chemotherapy would not be appropriate in her case and Answer D is incorrect.

Outcome of This Case

Our patient was initially started on fulvestrant. She achieved a near-complete radiologic response and a durable clinical response that lasted close to 2 years before her liver disease progressed. Chemotherapy and local therapy with SBRT were used at a later time for management of lesions close to the porta hepatis and once bulky liver disease developed.

In order to guide eligibility for clinical studies with targeted therapies, next-generation sequencing (NGS) was performed on one of the patient’s metastatic lesions. NGS has a high rate of discovering potentially targetable (actionable) mutations; however, many targeted therapies are currently considered experimental and are only available to patients in ongoing clinical trials.

Of note, NGS of our patient’s metastatic tumor did reveal a common activating mutation in the ER (D538G). The rate of ER mutations is considerably greater in metastatic lesions and in treated patients with tumor progression than it is in primary tumors or in treatment-naive patients. For instance, Jeselsohn et al demonstrated recurrent mutations in the ligand-binding domain in 12% of metastatic lesions and in 20% of patients who received an average of seven lines of treatment; similar mutations were not found in treatment-naive ER-positive primary lesions.[15] The next generation of selective ER down-regulators, which are currently in clinical trials, are being considered as the next line of therapy for our patient upon disease progression.

An additional alteration in IKBKE and amplification of RICTOR were identified in the patient’s metastatic lesions, pointing towards activation of the mammalian target of rapamycin (mTOR) pathway. Interestingly, the patient’s cancer did not respond to the standard-of-care combination of exemestane and everolimus. Clearly, one must use caution in interpreting NGS results. Most important, further research is needed for validation of actionable mutations found on whole-genome assays, as is now being done in the MATCH trial.[16]

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

E. David Crawford, MD, serves as Series Editor for Clinical Quandaries. Dr. Crawford is Professor of Surgery, Urology, and Radiation Oncology, and Head of the Section of Urologic Oncology at the University of Colorado School of Medicine; Chairman of the Prostate Conditions Education Council; and a member of ONCOLOGY's Editorial Board.

If you have a case that you feel has particular educational value, illustrating important points in diagnosis or treatment, you may send the concept to Dr. Crawford at david.crawford@ucdenver.edu for consideration for a future installment of Clinical Quandaries.

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