Locoregional Therapies for Primary and Metastatic Breast Cancer: AJR Expert Panel Narrative Review.

Minimally invasive locoregional therapies have a growing role in the multidisciplinary treatment of primary and metastatic breast cancer. Factors contributing to the expanding role of ablation for primary breast cancer include earlier diagnosis, when tumors are small, and increased longevity of patients whose condition precludes surgery. Cryoablation has emerged as the leading ablative modality for primary breast cancer owing to its wide availability, the lack of need for sedation, and the ability to monitor the ablation zone. Emerging evidence suggests that in patients with oligometastatic breast cancer, use of locoregional therapies to eradicate all disease sites may confer a survival advantage. Evidence also suggests that transarterial therapies-including chemoembolization, chemoperfusion, and radioembolization-may be helpful to some patients with advanced liver metastases from breast cancer, such as those with hepatic oligoprogression or those who cannot tolerate systemic therapy. However, the optimal modalities for treatment of oligometastatic and advanced metastatic disease remain unknown. Finally, locoregional therapies may produce tumor antigens that in combination with immunotherapy drive anti-tumor immunity. Although key trials are ongoing, additional prospective studies are needed to establish the inclusion of interventional oncology in societal breast cancer guidelines to support further clinical adoption and improved patient outcomes.

Cryoablation Without Excision for Low-Risk Early-Stage Breast Cancer: 3-Year Interim Analysis of Ipsilateral Breast Tumor Recurrence in the ICE3 Trial.

BACKGROUND: The ICE3 trial is designed to evaluate the safety and efficacy of breast cryoablation, enabling women older than 60 years with low-risk early-stage breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks. METHODS: The ICE3 trial is a prospective, multi-center, single-arm, non-randomized trial including women age 60 years or older with unifocal, ultrasound-visible invasive ductal carcinoma size 1.5 cm or smaller and classified as low to intermediate grade, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Ipsilateral breast tumor recurrence (IBTR) at 5 years was the primary outcome. A 3-year interim analysis of IBTR was performed, and the IBTR probability was estimated using the Kaplan-Meier method. RESULTS: Full eligibility for the study was met by 194 patients, who received successful cryoablation per protocol. The mean age was 75 years (range, 55-94 years). The mean tumor length was 8.1 mm (range, 8-14.9 mm), and the mean tumor width was 7.4 mm (range, 2.8-14 mm). During a mean follow-up period of 34.83 months, the IBTR rate was 2.06% (4/194 patients). Device-related adverse events were reported as mild in 18.4% and moderate in 2.4% of the patients. No severe device-related adverse events were reported. More than 95% of the patients and 98% of the physicians reported satisfaction with the cosmetic results at the clinical follow-up evaluation. CONCLUSIONS: Breast cryoablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Further study within a clinical trial or registry is needed to confirm cryoablation as a viable alternative to surgical excision for appropriately selected low-risk patients.

A Phase II Trial Exploring the Success of Cryoablation Therapy in the Treatment of Invasive Breast Carcinoma: Results from ACOSOG (Alliance) Z1072.

BACKGROUND: Cryoablation is a well-established technique to treat fibroadenomas. Pilot studies suggest this could be an effective non-surgical treatment for breast cancer. American College of Surgeons Oncology Group Z1072 is a phase II trial exploring the effectiveness of cryoablation in the treatment of breast cancers. METHODS: The primary endpoint of Z1072 was the rate of complete tumor ablation, defined as no remaining invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) on pathologic examination of the targeted lesion. A secondary objective was to evaluate the negative predictive value of magnetic resonance imaging (MRI) to determine residual IBC or DCIS. Eligible patients included those with unifocal invasive ductal breast cancer ≤2 cm, with <25 % intraductal component and tumor enhancement on MRI. A total of 19 centers contributed 99 patients, of which 86 patients (87 breast cancers) were evaluable for data analysis. RESULTS: Final pathology results, regardless of whether residual IBC/DCIS was in the targeted ablation zone or elsewhere in the breast, showed successful ablation in 66/87 (75.9 %) cancers. The 90 % confidence interval for the estimate of successful cryoablation was 67.1-83.2, with the one-sided lower-sided 90 % CI of 69.0. The negative predictive value of MRI was 81.2 % (90 % CI 71.4-88.8). When multifocal disease outside of the targeted cryoablation zone was not defined as an ablation failure, 80/87 (92 %) of the treated cancers had a successful cryoablation. CONCLUSION: Further studies with modifications on the Z1072 protocol could be considered to evaluate the role for cryoablation as a non-surgical treatment of early-stage breast cancer.

Advocating Nonsurgical Management of Patients With Small, Incidental Radial Scars at the Time of Needle Core Biopsy: A Study of 77 Cases.

CONTEXT: Radial scars are benign sclerosing lesions that are routinely excised when diagnosed in a needle core biopsy. Optimal management for patients with incidental and small (≤5 mm) radial scars is uncertain. OBJECTIVE: To assess pathologic upgrade of radial scars diagnosed in needle core biopsy samples and identify a subset of patients who could benefit from conservative management. DESIGN: Patients with a diagnosis of radial scar in a needle core biopsy who underwent excision of the biopsied area were identified. Radial scars greater than 5 mm in size and those with coexisting atypia, carcinoma, and papillary lesions were excluded. After histologic-radiographic correlation, rates of pathologic upgrade were assessed. RESULTS: Seventy-seven radial scars diagnosed in 66 patients were included. Overall, 9 of 77 (12%) showed upgrade to a high-risk lesion (6 lobular carcinoma in situ, 2 atypical ductal hyperplasia, 1 atypical lobular hyperplasia), while none (0%) showed upgrade to invasive carcinoma or ductal carcinoma in situ. One of 22 incidental radial scars (4.5%) showed upgrade on excision versus 6 of 36 (16.7%) for radial scars considered to be the radiographic target (P = .23). Older age was associated with upgrade (P < .001). CONCLUSIONS: No incidental or small (≤5 mm) radial scars excised revealed invasive carcinoma or ductal carcinoma in situ on excision. Provided there is good pathologic-radiologic concordance, it appears reasonable for these patients to be managed conservatively.

An unusual breast lesion: granular cell tumor of the breast with extensive chest wall invasion.

Granular cell tumors (GCT) are generally benign soft tissue tumors. When located in the breast, they may be misdiagnosed as more typical tumors, such as invasive ductal carcinoma, based on misleading clinical or radiologic features. GCTs are frequently found in the setting of a known malignancy. We report the case of a patient with a large infra-mammary fold GCT, the management of which required a multidisciplinary operative approach due to extensive chest wall invasion.

A randomized prospective study of lumpectomy margin assessment with use of MarginProbe in patients with nonpalpable breast malignancies.

BACKGROUND: The presence of tumor cells at the margins of breast lumpectomy specimens is associated with an increased risk of ipsilateral tumor recurrence. Twenty to 30 % of patients undergoing breast-conserving surgery require second procedures to achieve negative margins. This study evaluated the adjunctive use of the MarginProbe device (Dune Medical Devices Ltd, Caesarea, Israel) in providing real-time intraoperative assessment of lumpectomy margins. METHODS: This multicenter randomized trial enrolled patients with nonpalpable breast malignancies. The study evaluated MarginProbe use in addition to standard intraoperative methods for margin assessment. After specimen removal and inspection, patients were randomized to device or control arms. In the device arm, MarginProbe was used to examine the main lumpectomy specimens and direct additional excision of positive margins. Intraoperative imaging was used in both arms; no intraoperative pathology assessment was permitted. RESULTS: In total, 596 patients were enrolled. False-negative rates were 24.8 and 66.1 % and false-positive rates were 53.6 and 16.6 % in the device and control arms, respectively. All positive margins on positive main specimens were resected in 62 % (101 of 163) of cases in the device arm, versus 22 % (33 of 147) in the control arm (p < 0.001). A total of 19.8 % (59 of 298) of patients in the device arm underwent a reexcision procedure compared with 25.8 % (77 of 298) in the control arm (6 % absolute, 23 % relative reduction). The difference in tissue volume removed was not significant. CONCLUSIONS: Adjunctive use of the MarginProbe device during breast-conserving surgery improved surgeons' ability to identify and resect positive lumpectomy margins in the absence of intraoperative pathology assessment, reducing the number of patients requiring reexcision. MarginProbe may aid performance of breast-conserving surgery by reducing the burden of reexcision procedures for patients and the health care system.

Effectiveness of a noninvasive digital infrared thermal imaging system in the detection of breast cancer.

BACKGROUND: Digital infrared thermal imaging (DITI) has resurfaced in this era of modernized computer technology. Its role in the detection of breast cancer is evaluated. METHODS: In this prospective clinical trial, 92 patients for whom a breast biopsy was recommended based on prior mammogram or ultrasound underwent DITI. Three scores were generated: an overall risk score in the screening mode, a clinical score based on patient information, and a third assessment by artificial neural network. RESULTS: Sixty of 94 biopsies were malignant and 34 were benign. DITI identified 58 of 60 malignancies, with 97% sensitivity, 44% specificity, and 82% negative predictive value depending on the mode used. Compared to an overall risk score of 0, a score of 3 or greater was significantly more likely to be associated with malignancy (30% vs 90%, P < .03). CONCLUSION: DITI is a valuable adjunct to mammography and ultrasound, especially in women with dense breast parenchyma.

Sentinel node positivity rates with and without frozen section for breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is used to detect breast cancer axillary metastases. Some surgeons send the sentinel lymph node (SLN) for intraoperative frozen section (FS) to minimize delayed axillary dissections. There has been concern that FS may discard nodal tissue and thus underdiagnose small metastases. This study examines whether evaluation of SLN by FS increases the false-negative rate of SLNB. METHODS: A retrospective analysis of SLNB from 659 patients was conducted to determine the frequency of node positivity among SLNB subjected to both FS and permanent section (PS) versus PS alone. Statistical analysis was performed by the chi(2) square test, and a logistic regression model was applied to estimate the effect of final node positivity between the two groups. RESULTS: FS was performed in 327 patients and PS was performed in all 659 patients. Among patients undergoing both FS and PS (n = 327), the final node positivity rate was 33.0% compared with 19.6% among patients undergoing PS alone (n = 332). After adjustment for patient age, tumor diameter, grade, and hormone receptor status in a multivariate logistic regression model, there remained an increased likelihood of final node positivity for patients undergoing both procedures relative to PS alone (adjusted odds ratio, 2.1; 95% confidence interval, 1.3-3.6; P = .005). CONCLUSIONS: There was a higher rate of SLN positivity in specimens evaluated by both FS and PS. Therefore, evaluating SLN by FS does not underdiagnose small metastases nor produce a higher false-negative rate. Intraoperative FS offers the advantage of less delayed axillary dissections.

Intraoperative intraductal injection of methylene blue dye to assist in major duct excision.

Nipple discharge is not uncommon in women during their reproductive years. The etiology is benign in the majority of cases. Patients presenting with nipple discharge often require major duct excision (MDE) for accurate diagnosis and treatment. MDE is enhanced by the use of intraoperative injection of methylene blue dye into the discharging duct in order to aid visualization. Methylene blue dye-enhanced MDE has several advantages over traditional techniques. Methylene blue dye staining identifies the major discharging duct, as well as its side branches, which allows the surgeon to resect that specific ductal system only. This method allows neighboring major ducts to remain intact, preserving nipple function and permitting future cancer detection. Methylene blue-enhanced MDE allows the surgeon to more accurately determine the precise location and volume of tissue that needs to be excised. Lastly, methylene blue is both safe and inexpensive.

Inflammatory local recurrence after breast-conservation therapy for noninflammatory breast cancer.

Inflammatory local recurrence after breast-conserving therapy for noninflammatory breast cancer is uncommon and carries a poor prognosis. Over a 5-year period, 7 such cases were treated at the New York-Presbyterian Hospital/Weill-Cornell Medical Center. The characteristics of these 7 patients were compiled and are reviewed along with a discussion of inflammatory recurrence. Tumor size, location, histologic type, grade, stage, margin status, lymphovascular invasion (LVI), estrogen receptor (ER) status, progesterone receptor (PgR) status, adjuvant therapy, and/or radiation therapy at the time of primary treatment and at recurrence were analyzed. The median survival time was 79 months (range, 26-130 months) for patients initially ER-positive, compared with 23 months (range, 0-67 months) for initially ER-negative patients. The median survival for patients without lymph node involvement was 78 months (range, 26-130 months) compared with 41 months (range, 0-79 months) for those with nodal metastases. Survival time in this series of inflammatory local recurrences correlated with the ER status and lymph node involvement of the primary lesion. The optimal management for inflammatory local recurrence is a multimodality approach combining preoperative chemotherapy and surgery.

Multiple re-excisions versus mastectomy in patients with persistent residual disease following breast conservation surgery.

BACKGROUND: Persistently involved margins following breast conservation surgery (BCS) create a diagnostic dilemma regarding the recommendation of further BCS or mastectomy. METHODS: A retrospective review of 276 breast cancer patients who underwent BCS and required additional surgical treatment between 1990-2002 was performed. RESULTS: For treatment of persistently involved margins, 63% of subjects underwent re-excision the first time, 49% the second time, and 37% the third time. The incidence of residual carcinoma increased linearly with the number of initially involved margins (P = .03). Ductal carcinoma-in-situ (DCIS) or infiltrating lobular carcinoma (IFLC) primary histology was associated with a higher rate of residual cancer compared to invasive ductal carcinoma (IFDC) (62% vs. 69% vs. 54%, respectively, P = .56). A trend towards an increased risk of residual cancer in primary tumors > or =2 cm versus tumors under 2 cm was also evident (63%% vs. 50%, respectively, P = .38). CONCLUSIONS: Approximately half of patients repeatedly selected BCS over mastectomy. It is important to realistically discuss the probability of definitive resection with patients who are undergoing breast conservation with re-excision.

Ablative therapies for the treatment of malignant diseases of the breast.

BACKGROUND: Because widespread screening for breast cancer is detecting more women at younger ages and earlier stages, the need for minimally invasive, cosmetically preferable approaches to its treatment is growing. Ablative techniques are now being applied to the treatment of primary breast tumors, perhaps offering an alternative to surgical excision. Techniques available for breast cancer treatment include radiofrequency ablation, cryoablation, interstitial laser ablation, microwave thermotherapy, and focused ultrasound ablation. DATA SOURCES: Literature searches for breast and cryoablation, focused ultrasound ablation, interstitial laser ablation, microwave thermotherapy, and radiofrequency ablation were performed. Over 30 articles were identified and analyzed. CONCLUSIONS: It is cautiously optimistic that these therapies can be used as a routine adjunct in the treatment of selected breast cancers. The challenge will lie in the ability to identify multifocal disease and in situ carcinoma as well as to ensure complete and effective eradication of the breast cancer.

Do bone marrow micrometastases correlate with sentinel lymph node metastases in breast cancer patients?

BACKGROUND: Sentinel lymph node biopsies (SLNB) are used to detect axillary metastases as an important prognostic indicator for breast cancer patients. Bone marrow micrometastases (BMM) have also been shown to predict prognosis. This study examines whether SLNB and BMM are associated. STUDY DESIGN: A retrospective analysis was performed on 124 stages I to III breast cancer patients treated with mastectomy or lumpectomy, SLNB, and bone marrow aspiration between 1997 and 2003. SLNB were examined for the presence of metastases by hematoxylin and eosin (H&E) stains and also by immunohistochemistry (IHC) for lymph nodes negative by H&E. The kappa statistic was used to evaluate the association (agreement) between SLNB and BMM. RESULTS: In this study population, 36 patients (29%) had micrometastases detected in their bone marrow, and 51 patients (41%) had positive sentinel lymph nodes. Of the patients with positive BMM (n = 36), 53% (19 of 36) had positive SLNB (14 of 19 by H&E and 5 of 19 by IHC). In patients with negative BMM (n = 88), 36% (32 of 88) had a positive SLNB (27 of 32 by H&E and 5 of 32 by IHC). The kappa statistic and associated 95% confidence interval indicated poor agreement between SLNB and BMM (kappa = 0.15; 95% CI = -0.03, 0.32). CONCLUSIONS: There was poor agreement between axillary metastases and micrometastases detected in the bone marrow. This study suggests that BMM and axillary metastases are not concordant findings in most patients.

A comparison of the adverse reactions associated with isosulfan blue versus methylene blue dye in sentinel lymph node biopsy for breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is an established means of staging the axilla in patients with breast cancer. Recently, methylene blue dye has been shown to be an efficacious and cost-effective alternative to isosulfan blue. With the increasing popularity of SLNB, the potential complications of isosulfan blue use must be appreciated. METHODS: A literature search for English language articles available on MEDLINE from 1985 to November 2002 using the search terms allergy, allergic reaction, anaphylactic reactions, anaphylaxis, blue dye, breast cancer, isosulfan blue, methylene blue, and sentinel lymph node biopsy identified 24 reports. CONCLUSIONS: The use of isosulfan blue due for SLNB is associated with a significant number of allergic reactions, some of which are life-threatening. Because methylene blue dye has been shown to be equally effective and does not pose a serious risk of serious allergic reactions, it offers an improved technique above isosulfan blue dye for SLNB.

Locally recurrent breast cancer after conservation therapy.

BACKGROUND: Today, the majority of small invasive and noninvasive breast cancers are treated with breast conservation therapy (BCT). The incidence of local-regional recurrence (LRR) after BCT for stage 0, I, and II patients ranges between 5% and 22%. METHODS: A literature search for BCT, local recurrence, and regional recurrence was performed. Data from over 50 articles pertaining to the characteristics, risk factors, detection, management, and prognosis of these patients with LRR after BCT were collected and analyzed. RESULTS: Positive margins, high-grade ductal carcinoma in situ (DCIS), young age, and the absence of radiation therapy after BCT increase the risk for LRR. Prognosis at LRR is impacted by invasive versus noninvasive histology, size and stage, method of detection, and involvement of skin and/or axillary lymph nodes. The standard treatment is salvage mastectomy. CONCLUSIONS: The prognosis for LRR after BCT is favorable compared with patients with postmastectomy chest wall recurrence.

Two-year follow-up of areola-sparing mastectomy with immediate reconstruction.

OBJECTIVE: Areola-sparing mastectomy (ASM) is defined as resecting the nipple and any existing surgical biopsy scar, removing all breast parenchyma, and leaving a natural envelope of skin (including the areola), which improves the aesthetic result of immediate reconstruction. We previously demonstrated a <1% incidence of malignant involvement of the areola in a retrospective mastectomy series. Subsequently, we performed ASM on selected patients undergoing mastectomy. We report here our results from an ongoing study of ASM at our institution. METHODS: During a 20-month period, 17 ASMs with immediate reconstruction were performed on 12 patients. Patients were followed-up prospectively by the surgical oncologist for complications and recurrence. RESULTS: ASM was performed for breast cancer prophylaxis (n = 10), ductal carcinoma in situ (DCIS) (n = 4), and <2-cm peripheral infiltrating carcinoma (n = 3). The mean patient age was 47.7 years (range 37 to 61). Thirteen patients were reconstructed with tissue expanders and 4 with pedicle transverse rectus abdominus myocutaneous flaps. Ten patients underwent sentinel lymph node biopsy. None of the ten patients showed sentinel lymph node metastasis. Two patients with DCIS and microinvasion underwent subareolar touch-prep cytology, both of which were negative for malignancy. All mastectomy specimens had negative histologic margins. No patient received chemotherapy or radiation therapy. One postoperative consisted of a localized wound infection that resolved with oral antibiotics. At a median follow-up of 24 months (range 11 to 28), there were no instances of local or distant recurrence. CONCLUSIONS: Overall, we found that ASM with immediate reconstruction provides excellent aesthetic results with infrequent complications. Furthermore, in this small series we showed no recurrence at 2 years. We continue to offer ASM for selected patients including those desiring surgical breast cancer prophylaxis as well as those with DCIS or small peripheral infiltrating ductal carcinoma.

Ductal carcinoma in situ in a 27-year-old woman with McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a sporadic disorder characterized by the triad of irregularly edged hyperpigmented macules (café au lait spots); a slowly progressive bone disorder, polyostotic fibrous dysplasia, usually involving the base of the skull and the long bones; and luteinizing hormone-releasing hormone (LHRH)-independent precocious puberty. This case is the first report of a 27-year-old woman with ductal carcinoma in situ (DCIS) and Paget's disease of the nipple associated with MAS. The discussion focuses on two endocrine manifestations of this syndrome including precocious puberty and excess growth hormone secretion. In our patient, both her early puberty and pituitary adenoma, in association with MAS, resulted in excess production and secretion of estrogen and growth hormone. Both of these hormones function to stimulate breast growth and development. We hypothesize they are responsible for this patient's DCIS and Paget's disease of the nipple so early in life.

Bone marrow micrometastases and adjuvant treatment of breast cancer.

The immunohistochemical detection of epithelially derived cells in the bone marrow of patients with primary breast cancer has been shown to be associated with increased risk of distant relapse as well as higher rates of cancer-related death. Despite the correlation between bone marrow micrometastases and poor outcome in breast cancer patients, bone marrow status does not yet have an established role in patient management. In this prospective study, adjuvant therapy recommendations for 43 patients with stage I, II, or III breast cancer treated with lumpectomy or mastectomy, sentinel lymph node biopsy and/or axillary dissection, and intraoperative bone marrow aspiration were recorded. Recommendations were made by a multidisciplinary tumor board both blinded and unblinded to the results of the bone marrow aspiration. In our study, 10 of the 43 breast cancer patients were found to have bone marrow micrometastases. Four of these patients (40%) had axillary lymph node metastases. When blinded to the results of the bone marrow aspiration, the tumor board recommended adjuvant chemotherapy for these four node-positive patients, as well as two node-negative patients. When unblinded to the results of the bone marrow aspiration, the tumor board did not change its recommendations for any of these six patients. The remaining four node-negative, bone marrow-positive patients were not advised to have adjuvant chemotherapy by the tumor board when blinded to bone marrow status. However, once the tumor board was informed of the presence of bone marrow micrometastases, adjuvant chemotherapy was recommended for all of these patients. The results of this pilot study indicate that the presence of bone marrow micrometastases in breast cancer patients with stage I, II, or III disease does influence recommendations for adjuvant chemotherapy, particularly in patients with node-negative disease.

Areola-sparing mastectomy with immediate breast reconstruction.

Skin-sparing mastectomy with immediate breast reconstruction is a proved option for patients with early-stage breast cancer requiring mastectomy. Based on the authors' recent pathologic analysis of mastectomy specimens showing less than 1% malignant involvement of the areola, they have begun to perform areola-sparing mastectomies (ASMs) on a select group of patients. They report their results from an ongoing study of ASM at their institution. During a 20-month period, 17 ASMs with immediate reconstruction were performed on 12 patients. Mastectomy was performed for breast cancer prophylaxis (n = 10), ductal carcinoma in situ (n = 4), and less than 2 cm of peripheral infiltrating carcinoma (n = 3). The most frequent incision performed was intraareola (n = 13). Thirteen patients were reconstructed with tissue expanders and 4 with pedicled transverse rectus abdominis musculocutaneous flaps. There was 1 postoperative complication, which consisted of a localized wound infection. Overall the authors found that ASM with immediate reconstruction provides excellent aesthetic results with infrequent complications.