Effects of Neoadjuvant Chemotherapy on Benign Breast Lesions Compared to Cancers: Should an Additional Lesion on Magnetic Resonance Imaging Responding Similar to Cancer after Neoadjuvant Chemotherapy be Viewed with Suspicion?

INTRODUCTION

Neoadjuvant chemotherapy (NAC) has evolved in its role in therapy of both inoperable and operable breast cancer.[123] Potential advantages of NAC include improved outcomes in breast conservation therapy, reduction in size of inoperable cancers rendering them operable, decrease in mastectomy rates in patients with large cancers, decrease in the size of involved axillary nodes, and early treatment of micrometastatic disease.[1345678] The early assessment of tumor response to NAC also allows for a potential modification in the treatment plan and may affect long-term outcome.[6]

NAC has been reported to significantly change tumor morphology, grade, and receptor expression.[9] Reported findings include the loss of support in the tumor vasculature due to direct effects on endothelial cell function; lobular morphologic change due to decreased cellularity and increased fibrosis;[10] increased nuclear grade; changes in tubule formation and mitotic count; tumor cell enlargement; and altered inflammatory reaction.[51011] In addition to its effects on the pathologic tumor, NAC also leads to morphologic changes in the surrounding normal breast tissue as evidenced on histologic analysis.[5] The histologic changes induced by NAC in nonneoplastic breast tissue include fibrosis, diffuse lobular atrophy, intralobular fibrosis, and drug-induced mild epithelial atypia.[58]

Contrast-enhanced breast magnetic resonance imaging (MRI) has shown to accurately assess pathologic response to NAC.[1213141516171819] Contrast-enhanced breast MRI is valuable before, during, and/or after NAC to assess treatment response and the extent of residual disease before surgery.[20] Pre- and post-NAC contrast-enhanced MRI not only provides morphologic details of the tumor but also helps in assessing the enhancement characteristics based on the uptake of contrast agent into the tumor. It has been reported in some studies that tumors with a higher degree of pretreatment enhancement tend to have a better response to treatment.[192122] It is hypothesized that increased angiogenesis in these cases may favor accessibility of the chemotherapy within the tumor leading to an improved response.[19]

Background parenchymal enhancement (BPE) on MRI is a recognized phenomenon in which the breast parenchyma physiologically enhances after intravenous contrast administration. The degree of BPE can be variable and depends on the patient age, menopausal status,[232425] lactational status,[262728] phase of the menstrual cycle,[232930] and use of hormone replacement therapy.[303132] Other exogenous/technical factors that can affect apparent BPE include the type of MRI sequences and type of contrast agent used.[33] BPE can also be affected by treatment with NAC, radiation therapy, and endocrine therapies.

Although the effects of NAC (as seen on MRI) on breast cancers and BPE have been well studied in the previous literature, the effects of NAC on benign breast lesions have not been evaluated to the best of our knowledge. The lack of such data may lead to management dilemmas in certain clinical situations. In routine clinical practice, many times the patients with newly diagnosed breast cancer may show on MRI, additional benign appearing (Breast Imaging Reporting and Data System [BI-RADS] 2 or 3) lesions in the ipsilateral or contralateral breast that are not biopsied.[34] One may face a management dilemma when such a lesion responds to NAC in a similar fashion as known cancer. Since there is no data available, some radiologists or surgeons may prefer the excision of those lesions as well due to the suspicion of cancer-based on their similar response. Our study may be considered as a baseline study in this regard that will show how benign lesions respond to NAC treatment, and this may help in making appropriate management decisions.

METHODS

RESULTS

The mean patient age was 53 years; all were females, 55.4% were African-American, 40.4% were Caucasian, and 4.2% were hispanic. Of the 38 breast cancer patients who underwent NAC, pre- and post-NAC MRI and had an ipsilateral or contralateral benign breast biopsy, 37 (97%) had invasive ductal carcinoma and one patient (3%) had invasive lobular carcinoma. Among the 47 benign lesions, 27 (57.4%) lesions were classified as nonproliferative and 20 (42.6%) as proliferative. The effects of NAC in 38 cancers were compared to the effects of NAC in 47 benign lesions in these 38 patients.

Neoadjuvant chemotherapy effects on lesion size

Both cancers and the benign lesions showed a significant decrease in size (P < 0.001) after NAC (Figure 1 and Table 1). The mean cancer size decreased from 4.09 cm (±standard deviation [SD] =2.51 cm) on pre-NAC MRI to 1.54 cm (±SD = 2.32 cm) on the post-NAC MRI. The benign masses also showed a significant decrease in size from the mean size of 0.83 cm (±SD = 0.51 cm) on pre-NAC MRI to 0.28 cm (±SD = 0.51 cm) on post-NAC MRI (Figure 1 and Table 1). Although both benign and malignant lesions decreased in size after NAC, the size reduction in malignant lesions was significantly greater than in benign lesions [F (1, 46) =42.36, P < 0.001].

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Figure 1

Effects of neoadjuvant chemotherapy on the size and enhancement of malignant and benign lesions, background breast glandularity, and background parenchymal enhancement.

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Table 1 Pre- and post-neoadjuvant chemotherapy magnetic resonance imaging measurements of size (cm) and enhancement of cancer and biopsied benign lesions

Proliferative versus nonproliferative benign lesions

The size reduction from pre-NAC to post-NAC in nonproliferative lesions versus proliferative lesions was not significantly different (M = 0.53 cm, SD = 0.37 cm vs. M =0.59 cm, SD = 0.32 cm; P = 0.60) (Table 2). There was also no significant difference between the enhancement patterns (P = 0.27).

Table 2 Comparison between the patient groups showing benign nonproliferative and benign proliferative pathology

DISCUSSION

Breast MRI is considered helpful to determine the extent of disease in patients with known breast cancer, evaluate for occult malignancy, and assess response in breast cancer patients treated with NAC. MRI can detect occult disease in the ipsilateral breast in about 12–27% of patients and in the contralateral breast in about 4% of patients.[20] In evaluating the response to chemotherapy, breast MRI is better than the clinical examination or mammography.[12131516]

In patients with newly diagnosed breast cancer who receive an MRI, further management not only depends on the extent of known cancer but also on discovery of additional ipsilateral and/or contralateral lesions. Many times, additional work-up with targeted ultrasound and/or additional biopsies is recommended before either any definitive surgical treatment is provided or treatment with NAC is started. In general, an additional lesion having suspicious morphology/dynamic characteristics will be biopsied before the treatment to rule out additional malignancy if an additional cancer diagnosis will change the further management decision. However, the additional lesions having benign or probably benign morphology are frequently left unbiopsied, and many of these patients will proceed to NAC treatment for their cancers. A management dilemma may arise when such a lesion responds to the NAC in a similar fashion as the patient's known cancer responds. This may raise the radiologist's or clinician's level of suspicion about these unbiopsied lesions for possible additional cancer foci.

The results of our study demonstrate that NAC affects benign lesions in a similar fashion as it affects cancers [Figure 2]. Although the size reduction happens to a lesser degree compared to cancers, there is no significant difference in the degree of decrease in the lesion enhancement. The response of benign lesion to NAC can be explained based on the previous work of Yeh et al., and Moll and Chumas.[58] They showed histologic changes such as lobular atrophy, decreased cellularity, and increased fibrosis occurring in normal glandular tissue after NAC treatment. It can be postulated that the same processes can probably happen in benign lesions as well leading to a decrease in size. Since cancers are generally excessively cellular, their size reduction can be expected to be more than the benign lesions. In addition, NAC affects the endothelial lining of the vessels leading to loss of vascular support. Similar changes may be expected to be seen in benign lesions leading to decreased enhancement. Protopapa et al., reported a positive correlation between the degree of tumor angiogenesis and the efficacy of chemotherapy.[39] They proposed increased angiogenesis in a cancer leads to a better delivery of the chemotherapeutic agent within the tumor increasing its chemosensitivity. One may intuitively think that the proliferative benign lesions would be expected to respond more than the nonproliferative benign lesions because they tend have more cellularity and/or microvasculature. However, our study did not show any difference in response between proliferative and nonproliferative lesions. This could be due to a small sample size or a number of other factors in the tumor microenvironment that may affect the response to NAC.

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Figure 2

A 44-year-old female with a history of newly diagnosed left breast cancer at 3 o’clock position (a). Subtraction T1-axial images from the first dynamic sequence of bilateral contrast-enhanced breast magnetic resonance imaging before neoadjuvant chemotherapy (a and b) and after neoadjuvant chemotherapy (c and d) are shown. Another enhancing mass in the right breast (circled image b) was found to be a fibroadenoma on subsequent biopsy. Images c and d from the respective slices after neoadjuvant chemotherapy show disappearance of enhancement in cancer as well as benign lesion (fibroadenoma).

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Our study showed a significant decrease in BPE after NAC treatment [Figure 2a and c] which is consistent with the results reported in several previous studies.[40414243] Li et al., reported a decrease in BPE in both the treated and the untreated breast.[40] Due to the changes of lobular atrophy and fibrosis that occurs after the NAC, one may also expect an overall decrease in breast glandularity after NAC treatment. A decrease in breast glandularity after NAC was demonstrated by Chen et al.,[44] when they measured it by quantitative MRI technique. They showed a 10–16% decrease in amount of the glandular tissue after the NAC treatment. Our study did not show any significant decrease in glandularity which could be due to the fact that it was only visually assessed.

The limitations of our study include a small sample size and retrospective nature of the study. The other limitation was that the mean size of the benign lesions was smaller than the mean size of the malignant lesions which could have impacted on some of our results. A future larger study including larger benign lesions may give better comparative results.

CONCLUSION

Benign breast lesions also decrease in size and enhancement after NAC; however, the size reduction is to a lesser degree than breast cancers. Therefore, additional ipsilateral or contralateral lesions seen on preoperative MRI that respond to NAC similar to the patient's known cancer may not be assumed to be cancers. The management decisions should still rely on the initial level of suspicion.