Systemic treatment in breast cancer: a primer for radiologists

MDCT is the workhorse for monitoring metastatic breast cancer. Liver metastases occur in more than 50 % patients with breast cancer, and are seen as hypodense lesions. Restaging MDCT scans following systemic treatment typically show a reduction in size of the hypodense lesions in patients responding to treatment (Fig. 1). Non contrast images are useful in finding accurate tumour volume on follow-up MDCT [14]. At our institute, we routinely perform non-contrast imaging of the abdomen in all breast cancer patients, as breast cancer metastases can sometimes remain occult on the portal venous phase and can be better followed on non-contrast images on restaging scans [14]. The use of multiphasic CT with arterial and venous phase imaging has been shown to increase the detection rate of hypervascular liver metastasis, including those from breast, renal, and thyroid cancers, carcinoid tumours and melanoma [15]. There have been no large prospective studies analyzing the diagnostic accuracy of MDCT in assessing treatment response in liver metastasis from breast cancer. The Response Evaluation Criteria in Solid Tumours (RECIST) is the most widely accepted set of objective treatment response criteria [16, 17]. A recent retrospective study by He et al., however, showed that RECIST was inadequate for assessing response to targeted therapies in breast cancer liver metastasis. In their study of 39 patients with 68 liver lesions, while treatment with cytotoxic chemotherapy showed a decrease in both size and density of liver metastases, treatment with targeted therapies alone did not, although 2-year survival was better [18].

A classic finding seen in treated breast cancer metastases is hepatic capsular retraction, or “pseudocirrhosis” (Fig. 1). In patients undergoing chemotherapy, pseudocirrhosis has been documented as a form of treatment response, described as capsular retraction secondary to shrinkage and retraction of tumours. This finding occurs more often in larger than smaller hepatic lesions, suggesting that intrinsic pathologic characteristics such as tumour growth or fibrosis, rather than tumour response alone, may contribute to capsular retraction [19]. Treatment with molecular-targeted drugs can reduce the enhancement of hepatic metastatic lesions compared to adjacent liver parenchyma. This phenomenon, known as pseudoprogression, with the appearance of apparent new lesions or transient enlargement of existing lesions is frequently seen on post-treatment follow-up CT examinations (Fig. 2) [20]. Similarly, lytic osseous metastatic lesions show osteoblastic response after systemic therapy. Restaging scans may show apparent new sclerotic lesions due to osteoblastic treatment response, which can be confused as new bone metastases (pseudoprogression) (Fig. 3) [21, 22]. Clinical and biochemical correlation (tumours markers) helps to assess treatment response in such cases.

Thoracic metastases in breast cancer can involve pulmonary parenchyma, airways, pleura and thoracic lymph nodes [23]. Imaging patterns of lung parenchymal metastases from breast cancer include solitary or multiple lung nodules, endobronchial nodules, lymphangitic carcinomatosis and air–space consolidation. Pleural disease from breast cancer usually manifests as pleural nodularity, thickening and effusions. Metastatic parenchymal nodules are generally solid, spheric or ovoid in shape, sharply marginated, and located mostly in the periphery of the lung in contrast to other aetiologies such as infection or inflammation [23]. However, a solitary pulmonary nodule appearing in a patient with breast cancer is not always suggestive of metastatic disease, as more than 50 % of the nodules may have aetiologies such as primary lung tumour or other benign lesions, and histological confirmation is necessary [24]. Pulmonary nodules respond to systemic treatment with a reduction in size. Cavitation of pulmonary nodules is uncommonly seen as secondary to both cytotoxic chemotherapy and newer anti-angiogenic agents. To prevent misclassification as disease progression, alternative methods of measuring cavitary lesions (i.e. exclusion of the air component during measurement) have been described in the primary lung cancer literature [25].

Positron emission tomography (PET)/CT is a useful diagnostic modality in the event of equivocal findings on conventional staging techniques, especially in patients with locally advanced or metastatic disease [1]. In the neoadjuvant setting, a decrease in maximum standardized uptake value (SUV_max) of 60 % from baseline has shown up to 96 % specificity in predicting pathologic complete response (pCR) after just one course of chemotherapy (Fig. 7) [38]. This contributes important prognostic information, as patients with pCR have significantly higher disease-free and overall survival rates than non-responders. PET/CT is also valuable for detecting metabolic changes following treatment with antineoplastic agents. Prior to PET/CT, methods for monitoring therapeutic effectiveness were limited to physical exam or conventional imaging, thus relying on physical and morphological information. PET/CT is effective for monitoring physiological response after one treatment, prior to pathologic confirmation at the time of surgery, and thus decisions regarding the continuation or modification of therapy can be made early in the treatment course [39]. The pooled sensitivity and specificity of FDG-PET/CT in predicting histopathologic response in primary breast cancer is 81 and 79 %, respectively [40]. Similar to that of MRI, the performance of FDG-PET/CT in predicting pathologic complete response is better in HER2-positive and triple-negative tumours than in the luminal subtype [40]. In the metastatic setting, the sensitivity and specificity of FDG-PET/CT is 93 and 82 %, respectively [41]. The degree of reduction in FDG uptake in metastatic lesions after the first cycle of chemotherapy has been shown in some studies to differentiate responders from non-responders [41]. In evaluation of osseous metastasis, FDG-PET/CT can help in identifying viable metastases, as treated metastases become FDG-negative but remain osteoblastic on CT [41]. In cases of brain metastasis, FDG-PET is useful for differentiating between post-radiation necrosis and tumour recurrence [42]. One study found that dual-phase FDG-PET imaging of the brain was superior to the standard single-phase FDG-PET in differentiating recurrent metastasis from post-treatment necrosis [43].

Bone is the most common site of breast cancer metastasis. Bone scintigraphy is the most widely used modality for detecting bone metastases, and demonstrates osteoblastic activity as areas of increased radiotracer uptake. However, certain characteristic false-negative and false-positive findings on scintigraphy should be kept in mind in assessing treatment response. Scintigraphy sometimes demonstrates an apparent worsening of abnormalities, known as the “flare phenomenon,” characterized by increased activity in known lesions or new lesions during the first 3 months after treatment as a result of bone repair (Fig. 8) [44]. This finding should not be confused with progression of disease, and should be followed up with another bone scan in 4 to 6 months. A finding that persists beyond 6 months, however, is more likely indicative of disease progression. The apparent worsening or new sclerotic osseous lesions should be interpreted with caution, and should not be considered new or progressive disease, particularly in the setting of improving tumour markers and clinical status and the absence of other bone progression. The concept of increased osteoblastic healing reaction was introduced as a criterion for treatment response by the M.D. Anderson Cancer Center in 2004 [45]. In the revised criteria, CT and MRI are included as imaging modalities for assessing treatment response in bony metastases. The appearance of peripheral sclerosis around initial lytic lesions or sclerosis of previously undetectable lesions on CT or radiographs is considered a partial response. The rapid regression of lesions on scintigraphy was excluded as a partial response, as this finding may represent progression of lytic bony lesions. Bone scintigraphy is not sensitive for lytic osseous metastases given the low amount or absence of osteoblastic activity in these lesions. ¹⁸F-FDG PET is more sensitive than scintigraphy in detecting lytic metastases and marrow involvement [46]. The recently proposed PERCIST (PET Response Criteria in Solid Tumours) guidelines involve the role of FDG PET in treatment response, with an emphasis on change in tumour metabolism after therapy over anatomically based criteria [47].

CT is also helpful in monitoring treatment-related complications. Pulmonary toxicity is a common drug-related complication seen with taxanes and methotrexate. CT findings include pulmonary infiltrates presenting in early onset as bilateral reticular, ground-glass or consolidative opacities, pulmonary oedema, and pleural effusions, and as fibrosis in late disease (Fig. 9) [48]. Pulmonary infiltrates, however, are a non-specific finding, and can also result from disease progression and infection; thus clinical factors should also be taken into consideration.

Neutropenic enterocolitis and typhlitis (neutropenic enterocolitis of the cecum) are the most common GI side effects of chemotherapy, and are associated with several cytotoxic breast cancer drugs including doxorubicin, docetaxel, paclitaxel and platinum agents. CT findings include colonic wall thickening and oedema and/or necrosis, pericolonic fat stranding, ascites, pneumatosis intestinalis, and free air in the setting of bowel necrosis and perforation. While most frequently seen in the right colon, any colonic or small bowel segment can be involved. Because rapidly dividing GI mucosal cells are also vulnerable to cytotoxic agents, GI ulceration, which may further lead to perforation, is another treatment complication most commonly associated with doxorubicin and taxanes. Pneumatosis intestinalis may be observed with cyclophosphamide, doxorubicin, cisplatin and docetaxel [49].

Fluid retention, likely due to capillary protein leakage, has been seen in patients treated with docetaxel, and may manifest as peripheral oedema and as pleural and pericardial effusions [50]. Platinum-based agents carry an increased risk of thrombus formation [51]. Hemorrhagic cystitis is a well-known complication of cyclophosphamide, manifesting radiologically as diffuse thickening and nodularity of the bladder wall secondary to urothelial toxicity. This complication usually occurs early in treatment and is preventable with hydration and concurrent treatment with mesna, which neutralizes the toxic metabolic products within the bladder [52].

Patients receiving treatment with tamoxifen have an increased prevalence of endometrial hyperplasia, endometrial polyps and endometrial carcinoma (Fig. 10). Transvaginal ultrasound (US) and hysterosonography are useful tools for endometrial assessment, which is especially helpful in women treated with tamoxifen. While the agonistic effects of tamoxifen on estrogen receptors are beneficial in some tissues—for example, in lowering serum cholesterol and protecting against bone loss and cardiovascular disease—its proliferative effects on the uterine endometrium increase the risk of endometrial cancer [53]. On transvaginal US, endometrial carcinomas are typically diffusely or partially echogenic. As many patients treated on tamoxifen have endometrial thickening and underlying adenomyosis, poorly defined endometrial thickening is not a specific sign. Hysterosonography may be of further help in identifying an irregular, inhomogeneous mass or focal thickening in the endometrium [54]. Lack of distensibility of the endometrial cavity may also suggest carcinoma. MRI is useful for the characterization of endometrial abnormalities associated with tamoxifen therapy [55].

Tamoxifen causes hypercoagulability, increasing the risk of thromboembolic phenomena and catheter-related thrombosis (Fig. 8) [56].

Fatty liver is seen in up to 30 % of patients treated with tamoxifen (Fig. 11), and can be present as early as 3 months after initiation of treatment and can persist for more than 4 years after discontinuation [57]. Risk factors for hepatic changes associated with tamoxifen include preexisting conditions such as diabetes, obesity and hepatic steatosis. Fatty liver may rarely progress to steatohepatitis and cirrhosis. On ultrasound, hepatic steatosis presents as an echogenic liver, while on CT, the liver appears hypodense in comparison to the spleen (Fig. 9). On CT, fatty infiltration of the liver may obscure the presence of hypodense metastases. MR is helpful, as in-phase and out-of-phase imaging will demonstrate intracellular fatty deposition with signal dropout on out-of-phase sequences [58].

In postmenopausal women, the primary source of oestrogen is through conversion from adrenal androgen by aromatase. AIs prevent the conversion of androgens to estrogens, thereby causing a relatively rapid reduction in circulating oestrogen and an acceleration of bone loss at more than twice the rate of physiologic postmenopausal loss [59]. Regular bone marrow density monitoring is thus highly recommended. Bisphosphonates are the first line of therapy for the prevention and treatment of aromatase inhibitor-associated bone loss, as women on AIs are at increased risk of fractures [59].

MTTs have class-specific and drug-specific toxicities. m-TOR inhibitors such as everolimus are associated with drug-induced pneumonitis manifesting radiologically as ground-glass and consolidative opacities [48]. Radiation recall pneumonitis refers to an inflammatory reaction in the lungs within the previously treated radiation field after the start of chemotherapy, and can be seen occasionally with HER2 inhibitors (Fig. 12) [60]. Trastuzumab has been associated with cardiotoxicity, especially when administered with or after doxorubicin. The incidence of cardiac dysfunction in patients receiving trastuzumab ranges from 2 to 28 % [61]. The most common manifestation of trastuzumab cardiotoxicity is an asymptomatic decrease in left ventricular ejection fraction (LVEF) [62]. In contrast to doxorubicin-associated cardiotoxicity, trastuzumab-induced cardiotoxicity is not related to cumulative dose and is often reversible with discontinuation of treatment [63]. Multiple-gated acquisition (MUGA) scan and echocardiogram are used for determination of LVEF in breast cancer patients before and after chemotherapy [64]. The biochemical marker troponin I is also useful for monitoring cardiotoxicity as well as for identifying patients who are at risk for cardiotoxicity and less likely to recover [65]. Treatment discontinuation is recommended in patients with a greater than 16 % drop in LVEF compared to baseline or a decline in LVEF to below the lower limit of normal, and in patients who develop symptomatic cardiac failure [66]. Adverse effects of lapatinib include fatigue, nausea, rash, diarrhoea, neutropenia, hepatotoxicity, interstitial lung disease and pneumonitis [67].