Synchronous Bilateral Breast Cancer With Discordant Histology

April 15, 2017

A 48-year-old Caucasian woman presented with a palpable right breast mass. Physical examination confirmed a lump on the upper outer quadrant of her right breast. On PET/CT scan there was an incidental finding of increased metabolic activity in the left lateral breast.

The Case

A 48-year-old Caucasian woman presented with a palpable right breast mass. Physical examination confirmed a lump on the upper outer quadrant of her right breast. Mammogram showed bilateral dense breasts with abnormal microcalcifications. Ultrasound of the right breast revealed a 3.6-cm hypoechoic area, along with some abnormal-appearing axillary lymph nodes. Ultrasound-guided biopsy of the right breast lesion and one of the axillary lymph nodes showed an invasive ductal carcinoma, negative for estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors (Figure 1). Staging workup with positron emission tomography (PET)/CT confirmed the right breast lesion, with a maximum standardized uptake value (SUV) of 12, and multiple loci of right axillary nodal involvement, with an SUV of 4. There was no other uptake in the rest of the PET/CT scan; however, there was an incidental finding of increased metabolic activity in the left lateral breast, with an SUV of 4.7 (Figure 2). Further ultrasound examination of this area revealed some indeterminate hypoechoic abnormal-appearing tissue, approximately 3 cm in diameter. Ultrasound-guided needle biopsy of this area showed invasive lobular carcinoma, positive for estrogen receptor (99% of nuclei) and progesterone receptor (35% of nuclei); the HER2/neu immunohistochemistry score was 1+ (Figure 3). The patient’s mother had been diagnosed with breast cancer at the age of 65 years, and with colon cancer at age 70. Her family history was negative for Ashkenazi Jewish ancestry. Genetic testing for mutations in the BRCA1 and BRCA2 genes was negative.

Which of the following treatment plans has the least support from the available evidence?

A. Neoadjuvant chemotherapy followed by bilateral surgery (mastectomy or lumpectomy) with sentinel lymph node (SLN) evaluation on the left side, with or without completion axillary dissection even if SLN is positive; completion axillary dissection on the right side, followed by adjuvant chemotherapy, hormonal therapy, and unilateral or bilateral radiation therapy, depending on the surgical pathology results

B. SLN evaluation on the left side prior to neoadjuvant chemotherapy, with neoadjuvant chemotherapy followed by bilateral surgery (mastectomy or lumpectomy) with or without completion axillary dissection even if SLN is positive; completion axillary dissection on the right side, followed by adjuvant chemotherapy, hormonal therapy, and unilateral or bilateral radiation therapy, depending on the surgical pathology results

C. Bilateral surgery (mastectomy or lumpectomy) with SLN evaluation on the left side, with or without completion left axillary dissection even if SLN is positive; completion axillary dissection on the right side, followed by adjuvant chemotherapy, hormonal therapy, and unilateral or bilateral radiation therapy, depending on the surgical pathology results

D. Neoadjuvant concurrent chemotherapy and hormonal therapy, followed by bilateral surgery (mastectomy or lumpectomy) with SLN on the left side, with or without left axillary dissection even if SLN is positive; completion axillary dissection on the right side, followed by adjuvant chemotherapy, hormonal therapy, and unilateral or bilateral radiation therapy, depending on the surgical pathology results

Discussion

Here, we present a case of synchronous bilateral breast cancer with discordant histology and discordant response to therapy. The initial presentation was of a palpable right breast lump, which turned out to be a hormone receptor–negative, HER2-negative (triple-negative) clinical stage IIB (T2N1M0) invasive ductal carcinoma. During the staging workup of the initial right-sided breast cancer, a left breast abnormality was discovered on the PET/CT scan, leading to the diagnosis of a second primary breast cancer, which was a hormone receptor–positive, HER2-negative clinical stage IIA (T2N0M0) invasive lobular carcinoma. Treatment options for this complex clinical presentation can be quite variable.

Bilateral breast cancer can be synchronous or metachronous. The incidence rate of synchronous bilateral presentations is 1.0% to 2.6%, while the risk of developing metachronous contralateral carcinoma can be 0.9% per year, with a cumulative risk of 12% at 15 years. Second synchronous breast cancers are usually detected by mammography and are more frequently of the same histologic type as the index cancer.[1] Lobular histology, family history, young age at diagnosis of first cancer, and BRCA mutations have been associated with an increased incidence of bilateral presentation.[2] Breast cancer is a clinically and intrinsically heterogeneous disease. Observations of similar-histology breast tumors with different prognostic outcomes and different responses to treatment-in the same patient-have suggested variations in the genetic makeup of these tumors. Initial clinical and histopathologic classifications for breast cancer are now being replaced by molecular classification, which may shed light on these genetic differences.

Preoperative systemic therapy can render inoperable tumors resectable, and neoadjuvant chemotherapy was originally used in cases of locally advanced and inoperable tumors to improve surgical outcomes. Neoadjuvant chemotherapy has now been extended to operable breast cancer cases to facilitate breast-conserving surgery.[3] Neoadjuvant chemotherapy is also being considered increasingly for earlier-stage disease to evaluate the effect of chemotherapy on the primary tumor, with the information gained serving as a surrogate marker for predicting the effect of treatment on micrometastatic disease.[4-6] With regard to long-term outcomes, randomized clinical trials have found no significant differences whether systemic chemotherapy is given before or after surgery.[7,8] Other benefits of preoperative systemic therapy include allowing time for appropriate genetic testing and for breast reconstruction planning for patients who desire mastectomy. Furthermore, adjuvant chemotherapy options in clinical trials or as the standard care can be available for patients who have residual disease following neoadjuvant systemic therapy and surgery. Thus, none of the answers can be considered poorly supported by the evidence based on whether it features preoperative/neoadjuvant or postoperative/adjuvant systemic therapy.

Axillary lymph node dissection has largely been replaced by SLN biopsy for patients with clinically node-negative breast cancer; however, it is still required for a significant proportion of all breast cancer patients. Current indications for axillary node dissection include: a clinically node-positive axilla confirmed by fine-needle aspiration or core biopsy; occult breast cancer presenting as axillary node metastasis; SLN-positive patients who fall outside the American College of Surgeons Oncology Group (ACOSOG) Z0011 selection criteria (ie, tumor stage > T1 or T2, more than two positive SLNs, presence of extracapsular extension, or unwillingness to undergo whole-breast radiation therapy and adjuvant chemotherapy); inflammatory, clinical stage T4, or high-risk stage T3 breast cancer; and failed SLN mapping.[9] Because our patient presented with a biopsy-proven, clinically positive right axillary lymph node, she would need axillary node dissection on the right side. Since right axillary dissection is included in all answers, none can be considered poorly supported by the evidence in this regard. If a complete pathologic response was not achieved on the right side following neoadjuvant chemotherapy, the patient would be eligible for adjuvant capecitabine,[10] or she could be eligible for platinum-, poly(ADP-ribose) polymerase (PARP) inhibitor–, or checkpoint inhibitor–based adjuvant therapy clinical trials.

On the left side, since there was no clinical axillary nodal involvement, she would need to have an SLN procedure for surgical staging. If she were to choose lumpectomy and an SLN was found to be positive, based on the results of the ACOSOG Z0011 randomized trial, completion axillary node dissection would not significantly affect overall or disease-free survival.[11] If she were to choose mastectomy on the left side and the SLN was positive, she might need completion axillary dissection but could omit this if she was planning to have postmastectomy radiation.[12] Thus, none of the answers can be considered poorly supported by the evidence regarding management of the axilla on the left side either.

There is substantial literature showing that the success rate and accuracy of SLN biopsies performed before systemic neoadjuvant therapy are roughly comparable to the success rate and accuracy of procedures performed after neoadjuvant therapy. After systemic treatment, SLN biopsy has a lower detection rate and a higher false-negative rate compared with SLN biopsy done before neoadjuvant chemotherapy.[13,14] These limitations should be considered if biopsy is planned after neoadjuvant chemotherapy. Based on the available data, however, SLN biopsy either before or after neoadjuvant chemotherapy seems to be safe and reasonable for clinically node-negative patients-although when performed in conjunction with surgery, it has the added advantage of sparing patients another trip to the operating room. Still, none of the answers can be considered poorly supported by the available evidence on the basis of whether it features SLN biopsy before or after systemic neoadjuvant therapy.

Given that the left-sided breast cancer is hormone receptor–positive, adjuvant hormonal therapy is necessary. While randomized clinical trials have found no significant differences in long-term outcomes when systemic chemotherapy is given before or after surgery,[7,8] the same has not been shown clearly for systemic hormonal therapy. Furthermore, neoadjuvant chemotherapy with concurrent hormonal therapy has failed to provide significant improvements in pathologic complete response rates or survival outcomes in hormone receptor–positive breast cancers.[15,16] Currently, sequential use of hormonal therapy following chemotherapy remains the standard of care for hormone receptor–positive breast cancers until further studies can prove the superiority of a different approach. Answer D, therefore-which features concurrent neoadjuvant chemotherapy and hormonal therapy-is the treatment plan least well supported by the evidence.

Outcome of This Case

The patient was treated with a dose-dense regimen of neoadjuvant chemotherapy, consisting of 4 cycles of cyclophosphamide (600 mg/m2 IV) and doxorubicin (60 mg/m2 IV) followed by 4 cycles of paclitaxel (175 mg/m2 IV) every 2 weeks without any dose delays or dose reductions. Significant clinical response by the palpable tumor on the right side was noted during neoadjuvant chemotherapy. She chose to undergo bilateral mastectomy. Bilateral modified radical mastectomy with axillary lymph node dissection on the right side and SLN dissection on the left side was performed. Pathology showed a complete response, with no evidence of tumor in the right breast or right axillary nodes. A 4-cm residual tumor with one positive 0.4-cm SLN without soft-tissue extension was found on the left side. After excision of the previous SLN scar and evacuation of the seroma underneath, completion level I/II axillary dissection on the left side recovered four more lymph nodes without metastatic disease. The patient was treated with postmastectomy radiation and was prescribed a 5-year course of adjuvant hormonal therapy. She is 20 months out from the date of diagnosis and remains free of disease.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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.

References:

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14. Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013;310:1455-61.

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16. Rimawi MF, Cecchini RS, Rastogi P, et al. A phase III trial evaluating pCR in patients with HR+, HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) +/- estrogen deprivation: NRG Oncology/NSABP B-52. Presented at the 39th Annual San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Abstract S3-06.