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Journal of Clinical Oncology, Vol 25, No 18 (June 20), 2007: pp. 2618-2620 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.3084
Pathological Complete Response in Triple Negative Poorly Differentiated Invasive Ductal Breast Carcinoma Detected During PregnancyTu and Yuen Center for Functional Onco-Imaging, University of California, Irvine, CA
Tu and Yuen Center for Functional Onco-Imaging, University of California, Irvine, CA, and the Department of Radiology, China Medical University Hospital, Taichung, Taiwan
Department of Surgery, University of California, Irvine, CA
Department of Pathology, University of California, Irvine, CA
Department of Medicine, Division of Hematology/Oncology, University of California, Irvine, CA
Tu and Yuen Center for Functional Onco-Imaging, University of California, Irvine, CA A 32-year-old pregnant woman noted a rapidly growing lump in her right breast at about 10 weeks of pregnancy. The woman, however, attributed the changes in her breast to pregnancy. Five months later, at her thirtieth week of pregnancy, the lump was still growing. Concerned about her breast, she visited our hospital (UC Medical Center, Orange, CA). Initial physical examination revealed a large palpable mass measuring approximately 8 cm at 12 o'clock position of the right breast. No notable lymph nodes were found. Free-hand core biopsy revealed a poorly differentiated invasive ductal carcinoma (IDC). There were minimal tubules, a high degree of pleomorphism, and a moderate amount of mitoses (Fig 1A; original magnification x400). An atypical mitotic figure is seen in the lower part of the field and a highly atypical cell is present in the upper right. The tumor was a triple negative cancer, found to be negative for estrogen, progesterone, and human epidermal growth factor receptor 2 (HER-2) receptors. Treatment was deferred until fetal maturity of 34 weeks when she delivered a healthy male baby. A whole body positron emission tomography computed tomography scan performed immediately postpartum showed no evidence of metastatic lesions. Baseline ultrasonography revealed an ill-defined, heterogeneous mass measuring 7.9 cm in greatest dimension, with both echogenic and hypoechoic cystic areas. Considerable blood flow was seen within the solid portions of the mass. Because the mass was biopsy-proven IDC, it was labeled as Breast Imaging and Reporting Data System (BIRADS) category 6 tumor. A subsequent magnetic resonance imaging (MRI) scan showed a large, ill-defined 10-cm heterogeneously enhanced mass with several nonenhancing cystic areas and involvement of the overlying skin of the right breast (Fig 2A). A few axillary lymph nodes were also identified on sagittal images (Fig 3A). Time-dependent enhancement kinetic curve created from the mass lesion showed a typical malignant pattern with rapid initial upslope and followed by washout.
Given the diagnosis, the patient received neoadjuvant chemotherapy (NAC) consisting of four cycles of dose-dense doxorubicin and cyclophosphamide (AC) followed by four cycles abraxane (albumin bound form of paclitaxel), paclitaxel, carboplatin, and bevacizumab (AbCaAv). The patient refrained from breast feeding during the course of treatment. Mammography performed after two cycles of AC showed a BIRADS category 6 large mass at the 12 o'clock position with diffusely increased density of the right breast tissue. Further mammography performed after four cycles of AC and three AbCaAv showed progressive reduction in size and density of the mass lesion. Follow-up sonography performed after two cycles of AC, four cycles of AC, and three cycles of AbCaAv also revealed progressive decrease in lesion size from baseline dimension of 7.9 to 4.4 cm and 2.7 and 2.2 cm, respectively. However, the patient did not undergo mammography or ultrasound after completion of all chemotherapy. Serial follow-up magnetic resonance scans performed after two cycles and four cycles of AC, and three cycles and four cycles of AbCaAv showed a dramatic response. The tumor size decreased from 10 cm at baseline to 7 cm on the first follow-up (Fig 2B), with corresponding reduction in the size of lymph nodes (Fig 3B). On the second and third follow-up scans, the tumor size decreased to 2 cm (Fig 2C) and 1.6 cm, respectively. The fourth and final follow-up MRI performed after the completion of NAC, showed complete clinical response on MRI. Only a tiny focus of very low magnitude of enhancement similar to that of the background fibroglandular tissue was found in the region previously occupied by the tumor (Fig 2D). After the NAC completion, the patient underwent modified radical mastectomy of the right breast with concomitant excision of three sentinel nodes and 10 nonsentinel axillary nodes. Sections taken from the biopsy site of the mastectomy (Fig 1B; original magnification x100) show fibrosis, chronic inflammation, and foamy macrophages. There are hemosiderin-laden macrophages within fibrosis on the left side of the field, indicating the previous biopsy. Foamy macrophages can be seen on the right. Histopathologic examination of the mastectomy specimen and axillary nodes confirmed the absence of ductal carcinoma in situ or any residual tumor, and hence was compatible with a pathological complete response (PCR). Breast cancer is the most common cancer in pregnant and postpartum women, occurring in about 1 of 3,000 pregnant women. Patients are usually between 32 to 38 years of age (our patient was 32).1 Early full-term pregnancy is thought to be one of the most effective means of decreasing lifetime breast cancer risk. Paradoxically, young women diagnosed with breast cancer shortly after giving birth have a higher risk of dying from the disease.2 Studies have suggested that remodeling of the cellular microenvironment and extracellular matrix of the breast during pregnancy and involution may contribute to the enhanced invasive and metastatic potential of breast carcinomas and thus lead to a worsened clinical outcome.3 Tumor size and lymph node status are among the two most important independent but additive prognostic markers for breast tumor. As tumor size increases, survival decreases regardless of the lymph node status.4 In our case, the tumor was both large in size and also showed a cystic component, suggesting an aggressive tumor. Tumor growth may have been spurred by the hormone changes associated with pregnancy, leading to tumor necrosis.5 The tumor in our patient was negative for estrogen, progesterone, and HER-2 receptors, and hence was called a triple negative tumor. Triple negative tumors are associated with larger lesion size, pushing margin, a poorer Nottingham prognostic index, higher rate of recurrence and distant metastases, and poorer outcome in terms of overall survival and disease-free interval. In addition, HER-2–negative tumors lack the benefit of transtuzumab-based chemotherapy regimens, resulting in limited treatment options for triple negative tumors.6 To date, there is no standard method for grading the pathological response of breast tumors to neoadjuvant chemotherapy. A number of different classification systems have been proposed. Most grading schemes fall into the category of either no residual disease of any sort or residual ductal carcinoma in situ without invasive disease, in the definition of PCR.7,8 After completion of NAC, PCR is an important prognostic factor and is associated with fewer local and distant recurrences. Studies have shown a statistically significant difference in overall survival between patients whose tumors have a PCR compared with patients who have residual disease after chemotherapy. However, all patients undergoing primary chemotherapy should subsequently undergo surgery to ensure the complete removal of any residual tumor.9,10 A recent study performed at our institute on breast cancer treated with NAC has shown a statistically significant difference in achieving PCR between HER-2–positive and HER-2–negative tumors. After NAC, HER-2–negative patients had a lower chance of achieving PCR relative to patients with HER-2–positive tumors.10a In addition, MRI was found to have a significantly higher diagnostic rate for predicting PCR in HER-2–positive patients. Although the achieved PCR in this study was higher for the HER-2–positive group, a substantial percentage (35%) of HER-2 negative lesion also achieved PCR.11 The efficacy of bevacizumab, as part of combination therapy for breast cancer and other solid tumors, was recently demonstrated by Shih et al.12 In another study, the addition of bevacizumab to capecitabine produced a significant increase in the response rate for breast cancer patients.13 This case is unique owing to the fact that the patient had multiple poor prognostic indicators such as large tumor size, triple biomarker negativity, and a delayed diagnosis of undifferentiated ductal malignancy due to late presentation. However, she still achieved PCR by neoadjuvant chemotherapy with four cycles of AC followed by four cycles of AbCaAv regimen. MRI provided an accurate guide to tumor response and correctly predicted PCR. A recent study has also demonstrated the efficacy of ultrasound in diagnosing and after NAC response of pregnancy-associated breast cancer. In the study, two of 12 patients who received follow-up ultrasound scans for assessing chemotherapy response exhibited complete clinical response for tumor mass and partial response in the lymph nodes. However the authors did not correlate these specific imaging findings with pathological responses.14 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS Supported in part by National Institutes of Health/National Cancer Institute Grant No. R01 CA90437 and California BCRP # 9WB-0020. REFERENCES 1. National Cancer Institute: U.S. National Institutes of Health: Breast cancer and pregnancy. http://www.cancer.gov. 2. Daling JR, Malone KE, Doody DR, et al: The relation of reproductive factors to mortality from breast cancer. Cancer Epidemiol Biomarkers Prev 11:235-241, 2002 3. Polyak K: Pregnancy and breast cancer: The other side of the coin. Cancer Cell 9:151-153, 2006[CrossRef][Medline] 4. Carter CL, Allen C, Henson DE, et al: Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 63:181-187, 1989[CrossRef][Medline] 5. Ahn BY, Kim HH, Moon WK, et al: Pregnancy- and lactation-associated breast cancer: Mammographic and sonographic findings. J Ultrasound Med 22:491-497, 2003; quiz 22:498-499, 2003 6. Rakha EA, El-Sayed ME, Green AR, et al: Prognostic markers in triple-negative breast cancer. Cancer 109:25-32, 2007[CrossRef][Medline] 7. Jones RL, Lakhani SR, Ring AE, et al: Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma. Br J Cancer 94:358-362, 2006[CrossRef][Medline] 8. Buzdar AU, Ibrahim NK, Francis D, et al: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23:3676-3685, 2005 9. Machiavelli MR, Romero AO, Perez JE, et al: Prognostic significance of pathological response of primary tumor and metastatic axillary lymph nodes after neoadjuvant chemotherapy for locally advanced breast carcinoma. Cancer J Sci Am 4:125-131, 1998[Medline] 10. Chaturvedi S, McLaren C, Schofield AC, et al: Patterns of local and distant disease relapse in patients with breast cancer treated with primary chemotherapy: Do patients with a complete pathological response differ from those with residual tumour in the breast? Breast Cancer Res Treat 93:151-158, 2005[CrossRef][Medline] 10. Mehta RS, Schubbert T, Hsiang D, et al: High pathological complete remission rates with pacliataxel and carboplatin ± trastuzumab (TC±H) following dose dense doxorubicin and cyclophosphamide (AC) supported by GM-CSF in breast cancer: A phase II study. Breast Cancer Res Trt 29, 2005 (suppl 1; abstr 5056) 11. Chen JH, Su MY, Agrawal G, et al: MR imaging of pathological complete response following neoadjuvant chemotherapy. Annual Meeting of the International Society of Magnetic Resonance in Medicine, May 19-25, 2007, Berlin, Germany 12. Shih T, Lindley C: Bevacizumab: An angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 28:1779-1802, 2006[CrossRef][Medline] 13. Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792-799, 2005 14. Yang WT, Dryden MJ, Gwyn K, et al: Imaging of breast cancer diagnosed and treated with chemotherapy during pregnancy. Radiology 239:52-60, 2006 Related Correspondence
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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