Locally Advanced Breast Cancer and Neoadjuvant Chemotherapy: Implications for Breast Imaging
Written by: Debra M. Ikeda, M.D.
April 16, 2001

A recent approach to treating women with large Stage T3 or T4 breast cancers, with or without regional lymph node involvement, is the use of chemotherapy prior to surgery, or "neoadjuvant" chemotherapy (1-4). When followed by local treatment, surgery, and radiation, preoperative neoadjuvant chemotherapy results in a local response (reduction in size) of large breast tumors in up to 70%-90% of patients. Women with locally advanced disease undergoing neoadjuvant chemotherapy show improved disease-free and overall survival and comparable improvements have been reported for non-locally advanced disease.

While there is some variation, the vast majority of patients receiving neoadjuvant therapy at Stanford University Medical Center receive either CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) chemotherapy or AC (doxorubicin, cyclophosphamide) chemotherapy. Poor outcomes in patients with locally advanced cancer are usually due to distant micrometastatic disease at the time of diagnosis. Thus, the overall goal of treatment in this setting is to provide local control and improve overall survival.

Tumor response to neoadjuvant chemotherapy is assessed by breast physical examination, and is classified as no response (NR), partial response (PR) or complete response (CR). In one study, up to 73% of women with large T4 (inflammatory or locally advanced) carcinomas showed partial or complete clinical response to preoperative neoadjuvant chemotherapy (25 of 34, or 73.5%) (5).

A secondary effect of neoadjuvant chemotherapy is the possibility of lumpectomy and radiation (rather than mastectomy) in women whose tumors respond dramatically, and who then become candidates for appropriate breast-conserving therapies. This option is still under investigation. Even though lumpectomy may be a strategy for local control in these women, poor outcomes are still due to distant disease at the time of initial treatment (4). In cases where tumor response is sufficient for women to qualify as candidates for breast-conserving therapy, it is important to understand the limitations of mammography for surgical planning.

Mammography after Neoadjuvant Chemotherapy

Mammograms may show changes in decreasing or resolving breast cancer masses indicating chemotherapy response, but mammography is unreliable in detecting all residual cancer after chemotherapy. Helvie et al. studied 56 women who had mammograms before and after neoadjuvant chemotherapy. Almost all of the patients (54, 96%) had a complete (34, 61%) or partial (20, 36%) response. When comparing mammography to pathology, sensitivity for detecting residual carcinoma was higher with mammography than clinical examination (79% vs. 49%), but the mammographic specificity was lower (77% vs. 92%) and did not predict residual disease reliably (6).

What is seen on mammograms after chemotherapy? Are masses or calcifications more likely to disappear? Vinnicombe et al. showed that women with locally advanced cancer which manifested as calcifications on the mammogram usually did not have a complete response to neoadjuvant chemotherapy. Of 95 patients undergoing neoadjuvant chemotherapy, 8 showed a complete response (5 with residual tumor at surgery). A mammographic response was seen in 78 (82%) patients, 4 of whom had no residual disease at surgery. There was no response in 7 (7%) with one having no residual disease at surgery. Forty-four masses decreased in size to less than two cm. in diameter during chemotherapy. However, none of the 44 (46%) cases of microcalcifications had a complete response. The calcifications were fainter in four (9%), unchanged in 21 (48%), more condensed in 15 (34%), and increased in four (9%) cases. Of the eight cases with no residual cancer in the biopsy specimens, imaging studies showed a complete response in three masses, a mammographic response in two masses and two clustered calcifications, and a stable pattern of calcifications in the last case.

Thus, most patients showed some response to chemotherapy on mammography. Masses were most likely to respond on mammography, while calcifications tended to change a little, but were still present in most cases. Mammography was not accurate in predicting the absence of residual disease; masses or calcifications were still present in 5 of 8 cases in which no tumor was found at pathology (7).

Huber et al. reviewed masses versus calcifications in 44 Stage III breast cancer patients before and after neoadjuvant chemotherapy. He showed that tumors with well-defined borders could be assessed for a response more readily than obscured masses. Of 34 tumors, lesion borders correlated with tumor diameter on histopathological examination (r = 0.77) if greater than 50% of the border was defined on mammography. If less than 50% of the border of the mass was defined on mammography (14 tumors), mass size was poorly correlated with pathology (r = -0.19). The authors concluded that tumor response depended primarily on tumor visibility, and that ill-defined masses might be more accurately assessed with ultrasonography or magnetic resonance (MR) imaging (8).

Tumor Bed Markers and Imaging

Tissue marker clips are used in women undergoing neoadjuvant chemotherapy who have a significant clinical response. The tumor bed can be identified for breast-conserving surgery by the marker in cases of complete or almost complete tumor response. Of 24 women with clips placed by stereotaxis or ultrasound, Dash et al. found that preoperative localization would have been impossible (10 women, 35.7%) or difficult (6 women, 21.4%) without the clips in 16 patients, but that the clip was unnecessary in the remaining 8 patients (9). Edeiken et al. had similar results. Under ultrasound, these investigators placed metallic markers in 51 malignant breast tumors in 49 patients before neoadjuvant chemotherapy. The markers were the only remaining evidence of the original tumor site in 47% (23 of 49) of the patients (10). Thus, tissue marking clips can be useful in women with a marked clinical responses to chemotherapy.

The type of tumor marker may vary. Two articles describe the use of commercially available metallic markers placed into the tumor by ultrasound guidance. In one article, the clip used was for stereotactic core biopsy marking (Micromark Surgical Clip, Biopsys Medical, ref. 11), and in the other, the clip was used for vascular embolization (Hilal Embolization Coil, Cook, ref. 12).

Summary

Imaging after neoadjuvant chemotherapy can be tricky, particularly when the primary mammographic findings consist of calcifications. Since microcalcifications do not resolve with chemotherapy, and since imaging residual tumor can be difficult if the mass is obscured, mammography may not be the best choice to "clear" the breast for residual tumor. Tissue markers placed in the tumor for possible preoperative localization prior to neoadjuvant chemotherapy may be especially helpful if the tumor manifests as a mass and has a dramatic clinical response that results in complete resolution of the mammographic findings. Given these limitations, other imaging modalities, such as MRI, may prove useful in the future.

References:

1. Buzdar AU, Singletary SE, Booser DJ, Frye DK, Wasaff B, Hortobagyi GN. Combined modality treatment of stage III and inflammatory breast cancer. M.D. Anderson Cancer Center experience. Surg Oncol Clin N Am 1995; 4:715-34.
2. Chollet P, Charrier S, Brain E, Cure H, van Praagh I, Feillel V, de Latour M, Dauplat J, Misset JL, Ferriere JP. Clinical and pathological response to primary chemotherapy in operable breast cancer. Eur J Cancer 1997; 33:862-6.
3. Carlson R, Favret A. Multidisciplinary management of locally advanced breast cancer. The Breast Journal 1999; 5:303-7.
4. Schwartz GF, Cantor RI, Biermann WA. Neoadjuvant chemotherapy before definitive treatment for stage III carcinoma of the breast. Arch Surg 1987; 122:1430-4.
5. Yeh KA, Jillella AP, Wei JP. Surgery for T4 breast carcinoma: implications for local control. Am Surg 2000; 66:250-4; discussion 255.
6. Helvie MA, Joynt LK, Cody RL, Pierce LJ, Adler DD, Merajver SD. Locally advanced breast carcinoma: accuracy of mammography versus clinical examination in the prediction of residual disease after chemotherapy. Radiology 1996; 198:327-32.
7. Vinnicombe SJ, MacVicar AD, Guy RL, Sloane JP, Powles TJ, Knee G, Husband JE. Primary breast cancer: mammographic changes after neoadjuvant chemotherapy, with pathologic correlation. Radiology 1996; 198:333-40.
8. Huber S, Wagner M, Zuna I, Medl M, Czembirek H, Delorme S. Locally advanced breast carcinoma: evaluation of mammography in the prediction of residual disease after induction chemotherapy. Anticancer Res 2000; 20:553-8.
9. Dash N, Chafin SH, Johnson RR, Contractor FM. Usefulness of tissue marker clips in patients undergoing neoadjuvant chemotherapy for breast cancer. AJR 1999; 173:911-7.
10. Edeiken BS, Fornage BD, Bedi DG, Singletary SE, Ibrahim NK, Strom EA, Holmes F. US-guided implantation of metallic markers for permanent localization of the tumor bed in patients with breast cancer who undergo preoperative chemotherapy. Radiology 1999; 213:895-900.
11. Baron LF, Baron PL, Ackerman SJ, Durden DD, Pope TL, Jr. Sonographically guided clip placement facilitates localization of breast cancer after neoadjuvant chemotherapy. AJR 2000; 174:539-40.
12. Braeuning MP, Burke ET, Pisano ED. Embolization coils as tumor markers for mammography in patients undergoing neoadjuvant chemotherapy for carcinoma of the breast. AJR 2000; 174:251-2.