Prognostic value of HER2 status on circulating tumor cells in advanced-stage breast cancer patients with HER2-negative tumors.

PURPOSE: Discordance between HER2 expression in tumor tissue (tHER2) and HER2 status on circulating tumor cells (cHER2) has been reported. It remains largely underexplored whether patients with tHER2-/cHER2+ can benefit from anti-HER2 targeted therapies. METHODS: cHER2 status was determined in 105 advanced-stage patients with tHER2- breast tumors. Association between cHER2 status and progression-free survival (PFS) was analyzed by univariate and multivariate Cox models and survival differences were compared by Kaplan-Meier method. RESULTS: Compared to the patients with low-risk cHER2 (cHER2+ < 2), those with high-risk cHER2 (cHER2+ ≥ 2) had shorter survival time and an increased risk for disease progression (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.20-3.88, P = 0.010). Among the patients with high-risk cHER2, those who received anti-HER2 targeted therapies had improved PFS compared with those who did not (HR 0.30, 95% CI 0.10-0.92, P = 0.035). In comparison, anti-HER2 targeted therapy did not affect PFS among those with low-risk cHER2 (HR 0.70, 95% CI 0.36-1.38, P = 0.306). Similar results were obtained after adjusting covariates. A longitudinal analysis of 67 patients with cHER2 detected during follow-ups found that those whose cHER2 status changed from high-risk at baseline to low-risk at first follow-up exhibited a significantly improved survival compared to those whose cHER2 remained high-risk (median PFS: 11.7 weeks vs. 2.0 weeks, log-rank P = 0.001). CONCLUSION: In advanced-stage breast cancer patients with tHER2- tumors, cHER2 status has the potential to guide the use of anti-HER2 targeted therapy in patients with high-risk cHER2.

Is radial scar on core needle biopsy a risk factor for malignancy? A single-center retrospective review and implications for management.

INTRODUCTION: Reported upgrade rate to malignancy of radial scars (RS) ranges widely (0%-40%) making management controversial. METHODS: A retrospective chart review was performed on patients with RS on core needle biopsy (CNB). Upgrade rates to malignancy and atypia on surgical excision were evaluated. RESULTS: Of 127 patients with RS on CNB, 53 were excluded due to malignancy or missing records. Of 74 patients reviewed, 52 (70.3%) had surgical excision with four (7.7%) upgraded to malignancy. Eight patients (10.8%) had atypia with RS on CNB with two (25%) upgraded to malignancy. When isolated RS was on CNB, 2 of 44 (4.5%) upgraded to malignancy while 15 of 44 (34%) had atypia on excision. Of 22 patients (29.7%) who did not have excision, zero developed cancer. CONCLUSION: We found higher than expected upgrade rates of isolated RS to atypia which can alter management. Additionally, 25% of RS with atypia upgraded to malignancy suggesting these patients are at higher risk.

A Randomized, Controlled Trial of Cavity Shave Margins in Breast Cancer.

BACKGROUND: Routine resection of cavity shave margins (additional tissue circumferentially around the cavity left by partial mastectomy) may reduce the rates of positive margins (margins positive for tumor) and reexcision among patients undergoing partial mastectomy for breast cancer. METHODS: In this randomized, controlled trial, we assigned, in a 1:1 ratio, 235 patients with breast cancer of stage 0 to III who were undergoing partial mastectomy, with or without resection of selective margins, to have further cavity shave margins resected (shave group) or not to have further cavity shave margins resected (no-shave group). Randomization occurred intraoperatively after surgeons had completed standard partial mastectomy. Positive margins were defined as tumor touching the edge of the specimen that was removed in the case of invasive cancer and tumor that was within 1 mm of the edge of the specimen removed in the case of ductal carcinoma in situ. The rate of positive margins was the primary outcome measure; secondary outcome measures included cosmesis and the volume of tissue resected. RESULTS: The median age of the patients was 61 years (range, 33 to 94). On final pathological testing, 54 patients (23%) had invasive cancer, 45 (19%) had ductal carcinoma in situ, and 125 (53%) had both; 11 patients had no further disease. The median size of the tumor in the greatest diameter was 1.1 cm (range, 0 to 6.5) in patients with invasive carcinoma and 1.0 cm (range, 0 to 9.3) in patients with ductal carcinoma in situ. Groups were well matched at baseline with respect to demographic and clinicopathological characteristics. The rate of positive margins after partial mastectomy (before randomization) was similar in the shave group and the no-shave group (36% and 34%, respectively; P=0.69). After randomization, patients in the shave group had a significantly lower rate of positive margins than did those in the no-shave group (19% vs. 34%, P=0.01), as well as a lower rate of second surgery for margin clearance (10% vs. 21%, P=0.02). There was no significant difference in complications between the two groups. CONCLUSIONS: Cavity shaving halved the rates of positive margins and reexcision among patients with partial mastectomy. (Funded by the Yale Cancer Center; ClinicalTrials.gov number, NCT01452399.).

Frozen section evaluation of breast carcinoma sentinel lymph nodes: a retrospective review of 1,940 cases.

Many sentinel lymph node biopsies (SLNBs) are evaluated intraoperatively by frozen section, which may impact the need for further axillary dissection (AD). However, the need for AD in patients with small metastases has been recently called into question, meaning that frozen SLNB may be unnecessary. Furthermore, frozen section can compromise tissue for further study. At our institution, we grossly evaluate all SLNB and freeze half of the node. Here, we evaluate the frozen SLNB discrepancy rate using this method, focusing on cause of discrepancy and need for further surgery. We reviewed surgical pathology records for all breast cancer resections with frozen section of SLNB examined from 2003 to 2012. For cases with a frozen section discrepancy, we compiled clinicopathologic data. In total, 1,940 cases involved frozen section evaluation of SLNB. In 95 cases (4.9% of total cases, 23.8% of positive node cases), the SLNB was called negative on frozen but positive on final examination (false negatives). The majority of missed metastases are isolated tumor cells or micrometastases. A trend was observed toward fewer patients receiving completion AD after a discrepant frozen SLNB in the later years of the study. The protocol of freezing half of a SLNB is a reasonable method, with results similar to or better than other studies. The main adverse outcome is the need for separate AD; however, additional positive nodes are uncommon. The trend of fewer patients getting additional AD after a discrepant frozen SLNB suggests that clinicians may be using this information differently recently.

The number of lymph nodes dissected in breast cancer patients influences the accuracy of prognosis.

BACKGROUND: Recent trials have suggested that axillary node dissection may not be warranted in some breast cancer patients with one to two positive nodes. Given that lymph node ratio (LNR; number of positive lymph nodes divided by the total examined) has been shown to be a significant prognostic factor, we sought to determine whether the number of nodes removed in this low risk population predicted survival. METHODS: The National Cancer Database is a comprehensive clinical surveillance resource capturing 70% of newly diagnosed malignancies in the United States; 309,216 breast cancer patients diagnosed between 1998 and 2005, with tumors ≤5 cm and one to two positive nodes, formed the cohort of interest. RESULTS: Median age at diagnosis was 57 (range 18-90) years. Median tumor size was 2 (range 0.1-5) cm; 215,382 patients (69.7%) had one positive node, and 93,834 (30.3%) had two. The median number of lymph nodes examined was 11 (range 1-84). Patients were categorized into low (≤0.2), medium (0.21-0.65), or high (>0.65) LNR groups, with 228,822 (74%), 55,797 (18%), and 24,597 (8%) patients in each of these categories, respectively. Median follow-up was 54.1 months. Median overall survival (OS) for low, intermediate, and high LNR was 66.1, 61.1, and 56.5 months, respectively (p < 0.001). In a Cox model controlling for clinicopathologic and therapy covariates, LNR category remained a significant predictor of OS (p < 0.001). CONCLUSIONS: LNR is an independent predictor of OS in a low-risk population with one to two positive nodes and tumors ≤5 cm. Therefore, the number of lymph nodes excised may influence prognostic stratification.

A unique proteolytic fragment of alpha1-antitrypsin is elevated in ductal fluid of breast cancer patient.

By comparison of mass spectra from a small cohort of nipple aspiration fluids (NAF), we previously discovered a panel of five candidate breast cancer biomarkers among them an unidentified 4.7 kD peptide BF5. The purposes of the present study were to verify the presence of BF5 in an independent cohort; to determine the protein identity of BF5; and to provide insight into the biology of BF5 production and elevation in tumor-associated NAF. We prospectively collected bilaterally matched NAF from patients with unilateral Stage I/II breast cancer (IBC-31), ductal carcinoma in situ (DCIS-6), atypical ductal hyperplasia (ADH-5), and presumed healthy women who came to routine mammography and had a normal exam (31). Following the consolidation of its cancer-associated expression on SELDI-mass spectrometry, BF5 was isolated by gel electrophoresis and sequenced by tandem mass spectrometry. BF5 was elevated in 15-25% of women with IBC, DCIS, or ADH vs. 0% of controls. This elevation was restricted to the affected breasts. BF5 was identified as 41/42-aa C-terminal peptide of alpha1-antitrypsin (AAT), the principle inhibitor of serine protease neutrophile elastase. The full length AAT showed a consistent expression pattern as C-41/42, and C-41/42 can be generated in vitro by MMP-7 cleavage. In conclusion, elevated C-41/42 is likely the result of elevated AAT synthesis, and the activity of specific MMPs present within the tumor. As other C-terminal fragments of AAT are reported to function as tumor-derived suppressors to the host immune-system, elevated C-41/42 may also be predictive of a poor outcome.

Association of clinical outcomes in metastatic breast cancer patients with circulating tumour cell and circulating cell-free DNA.

BACKGROUND: Both circulating tumour cell (CTC) and total circulating cell-free DNA (ccfDNA) predict cancer patient prognosis. However, no study has explored the prognostic value of the combined use of CTC and ccfDNA. We aimed to investigate individual and joint effects of CTC and ccfDNA on clinical outcomes of metastatic breast cancer (MBC) patients. METHODS: We collected 227 blood samples from 117 MBC patients. CTCs were enumerated using the CellSearch System. ccfDNAs were quantified by quantitative real-time polymerase chain reaction and Qubit fluorometer. The individual and joint effects of CTC and ccfDNA levels on patient progression-free survival (PFS) and overall survival (OS) were analysed using Cox proportional hazards models. RESULTS: Compared to patients with <5 CTCs, patients with ≥5 CTCs had a 2.58-fold increased risk of progression and 3.63-fold increased risk of death. High level of ccfDNA was associated with a 2.05-fold increased risk of progression and 3.56-fold increased risk of death. These associations remained significant after adjusting for other important clinical covariates and CTC/ccfDNA levels. CTC and ccfDNA levels had a joint effect on patient outcomes. Compared to patients with low levels of both CTC and ccfDNA, those with high levels of both markers exhibited a >17-fold increased death risk (P < 0.001). Moreover, longitudinal analysis of 132 samples from 22 patients suggested that the inconsistency between CTC level and outcome in some patients could possibly be explained by ccfDNA level. CONCLUSIONS: CTC and total ccfDNA levels were individually and jointly associated with PFS and OS in MBC patients.

The superficial margin of the skin-sparing mastectomy for breast carcinoma: factors predicting involvement and efficacy of additional margin sampling.

BACKGROUND: No study has systematically evaluated the significance of involvement of the superficial specimen margin in skin-sparing mastectomies (SSMs). METHODS: 168 SSMs with a small, additional superficial margin (ASM) specimen taken directly over the tumor to the dermis intraoperatively were studied. RESULTS: 64 SSMs (38%) had a positive superficial specimen margin but only 13 (20%) of these had residual breast carcinoma in ASMs. Only 1 of 104 SSMs with a negative superficial specimen margin had residual breast carcinoma in its ASM (P < 0.05). ASM sampling rendered the final true margin directly over the tumor negative in 54 of 58 (93%) SSMs with a focally positive superficial specimen margin, but did not negate the nonfocally positive superficial specimen margin in six other cases. In SSMs with a positive superficial specimen margin, multivariate analysis revealed that the presence of extensive ductal carcinoma in situ (DCIS) in the SSM and a thicker ASM specimen were the only independent factors predictive of residual breast carcinoma in ASM. Eighty-nine (53%) ASMs contained benign breast tissue. CONCLUSIONS: Superficial specimen margins in SSMs are often microscopically positive and approximately half of ASMs contain benign breast tissue, likely reflecting the difficulty in completely removing breast tissue near the skin flaps in SSMs. ASM sampling effectively decreases positive superficial specimen margins directly over the tumor in SSMs, but fails to account for positive superficial specimen margins in other quadrants in patients with multicentric disease, especially extensive DCIS. Patients whose superficial margins remain positive could potentially represent a subset of patients for whom postmastectomy radiation is beneficial.

Nipple-sparing mastectomy: critical assessment of 51 procedures and implications for selection criteria.

BACKGROUND: Retrospective studies have shown that occult nipple-areolar complex (NAC) involvement in breast cancer is low, occurring in 6-10% of women undergoing skin-sparing mastectomy (SSM). The cosmetic result and high patient satisfaction of nipple-sparing mastectomy (NSM) has prompted further evaluation of the oncologic safety of this procedure. METHODS: We conducted a retrospective chart review of 36 self-selected patients who underwent 51 NSM procedures between 2002 and 2007. Criterion for patient selection was no clinical evidence of nipple-areolar tumor involvement. All patients had the base of the NAC evaluated for occult tumor by permanent histologic section assessment. We also evaluated tumor size, location, axillary node status, recurrence rate, and cosmetic result. RESULTS: Malignant NAC involvement was found in 2 of 34 NSM (5.9%) completed for cancer which prompted subsequent removal of the NAC. Of the 51 NSM, 17 were for prophylaxis, 10 for ductal carcinoma in situ (DCIS), and 24 for invasive cancer. The average tumor size was 2.8 cm for invasive cancer and 2.5 cm for DCIS. Nine patients had positive axillary nodes. Overall, 94% of the tumors were located peripherally in the breast. After mean follow-up of 18 months, only two patients (5.9%) had local recurrence. CONCLUSION: Using careful patient selection and careful pathological evaluation of the subareolar breast tissue at surgery, NSM can be an oncologically safe procedure in patients where this is important to their quality of life. A prospective study based on focused selection criteria and long-term follow-up is currently in progress.

The role of breast MRI in the management of patients with breast disease.

Breast MRI has paved the way for new thinking regarding the workup of women recently diagnosed with breast cancer and the screening of high-risk women. The routine use of MRI preoperatively is advocated, particularly in young patients and women with dense breasts where mammography is significantly less sensitive for the detection of malignancy. Additionally, MRI is particularly helpful in those women who have core biopsy results showing extensive intraductal component (>25%) orinvasive lobular carcinoma, and in those women with increased risk of positive margins. However, as with any imaging modality, breast magnetic resonance has limitations. Because breast magnetic resonance has lower specificity than some modalities, clinicians must be selective in identifying those women most likely to benefit from this additional imaging. Many recent publications show that MRI does not unduly raise the false-positive biopsy rate while providing specificity similar to that of mammography and higher than that of ultrasound. Positive margin rates for breast conservation therapy range from 30% to 50% and the achievement of negative margins is directly related to low recurrence rates. Magnetic resonance provides improved preoperative staging, which in turn may reduce recurrence rates and improve patient outcome. Breast MRI should be used in concert with other modalities, such as mammography and ultrasound, for the highest sensitivity for detecting malignancy. Long-term studies are needed to validate the impact of screening and diagnostic breast MRI on patient outcomes.

Do All Positive Margins in Breast Cancer Patients Undergoing a Partial Mastectomy Need to Be Resected?

BACKGROUND: Positive margins have been reported in 20% to 40% of patients undergoing a partial mastectomy, often resulting in re-excision. How often the re-excision yields additional cancer and whether there are predictors of residual disease remain unknown. STUDY DESIGN: Patients who had a positive margin (defined as tumor at ink for patients with invasive disease or within 1 mm for patients with ductal carcinoma in situ) in the SHAVE (A Randomized Controlled Trial of Routine Shave Margins Versus Standard Partial Mastectomy in Breast Cancer Patients) trial before randomization were evaluated to determine the rate of additional disease either in cavity shave margins or at re-excision. Details of the SHAVE trial can be found elsewhere. RESULTS: Of the 235 patients in the trial, 82 (34.9%) had a positive margin before randomization; 58 of these patients underwent either cavity shave margins excision or a re-excision of the positive margin(s). Twenty-one (36.2%) patients had residual disease. On bivariate analysis, residual disease was associated with younger patient age (median 51 vs 62 years; p = 0.007), and the presence of high-grade ductal carcinoma in situ (57.1% vs 31.3% for grade 2 and 0% for grade 1; p = 0.025). The following factors were not associated with further disease: patient race; ethnicity; BMI; volume of resection; number of positive margins; extent of ductal carcinoma in situ; and extent, grade, and histologic subtype of invasive cancer. On multivariate analysis, only patient age younger than 60 years remained a significant predictor of residual disease (odds ratio 3.920; 95% CI 1.081 to 14.220; p = 0.038). CONCLUSIONS: Positive margins are associated with further disease in more than one-third of patients and, aside from young age, there are no predictors of this. These findings support continued re-excision of positive margins, particularly in patients younger than 60 years of age.

Quality-of-Life Outcomes Improve with Nipple-Sparing Mastectomy and Breast Reconstruction.

BACKGROUND: Loss of the nipple-areola complex can be psychologically and sexually devastating. Nipple-sparing mastectomy provides robust cosmetic results, but few studies have investigated the quality-of-life outcomes associated with it. METHODS: The authors performed an institutional review board-approved retrospective study of 32 patients who underwent nipple-sparing mastectomy with implant-based or autologous reconstruction and 32 control patients who underwent non-nipple-sparing mastectomy with reconstruction matched by reconstruction type and operative period. They then compared premastectomy and postreconstruction responses to the BREAST-Q, a validated and breast reconstruction-specific quality-of-life questionnaire, within and between their study and control populations. RESULTS: The nipple-sparing and non-nipple-sparing mastectomy groups were statistically similar in terms of mean age [49.9 ± 8.5 years (range, 36 to 69 years) and 47.7 ± 10.3 years (range, 26 to 68 years) (p = 0.29), respectively] and mean body mass index [24.3 ± 3.5 kg/m (range, 17.9 to 33.7 kg/m) and 25.5 ± 5.4 kg/m (range, 19.2 to 39.2 kg/m) (p = 0.29), respectively]. There were no significant between-group differences in occurrence of postreconstruction complications. The authors found significantly higher mean postreconstruction scores in the nipple-sparing mastectomy group within the Satisfaction with Breasts (p = 0.039) and the Satisfaction with Outcome (p = 0.017) domains. Finally, they noted higher median postreconstruction scores in the nipple-sparing mastectomy group within the Psychosocial Well-being (p = 0.043) and Satisfaction with Breasts (p = 0.004) domains. CONCLUSIONS: Psychological concerns regarding malignancy may negatively impact premastectomy patient quality of life. Reconstructive surgery improves patients' postmastectomy quality of life. Nipple-sparing mastectomy appears to provide significantly better improvement in postreconstruction quality of life, specifically in the Satisfaction with Breasts and Satisfaction with Outcome domains of the BREAST-Q, compared with non-nipple-sparing mastectomies. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Reflex Estrogen Receptor (ER) and Progesterone Receptor (PR) Analysis of Ductal Carcinoma In Situ (DCIS) in Breast Needle Core Biopsy Specimens: An Unnecessary Exercise That Costs the United States $35 Million/y.

Most institutions reflexively test all breast core needle biopsy specimens showing ductal carcinoma in situ (DCIS) for estrogen receptor (ER) and progesterone receptor (PR). However, 5 factors suggest that this reflex testing unnecessarily increases costs. First, ER/PR results do not currently impact the next step in standard therapy; namely, surgical excision. Second, a subset of surgical excisions performed for DCIS diagnosed on core needle biopsy will harbor infiltrating mammary carcinoma, which will then need to be retested for ER/PR. Third, because ER and PR labeling is often heterogeneous in DCIS, negative results for ER/PR on small core needle biopsy specimens should logically be repeated on surgical excision specimens with larger amounts of DCIS to be sure that the result is truly negative. Fourth, many patients with pure ER/PR-positive DCIS after surgical excision will decline hormone therapy, so any ER/PR testing of their DCIS is unnecessary. Fifth, PR status in DCIS has no proven independent value. We now examine the unnecessary added costs associated with reflex ER/PR testing of DCIS on core needle biopsy specimens due to these factors. We reviewed 58 core needle biopsies showing pure DCIS that also had a resulting surgical excision specimen at our institution over a period of 2 years. No patient received neoadjuvant hormone therapy. On surgical excision, 5 (8.6%) had only benign findings, 44 (75.9%) had pure DCIS, and 9 (15.5%) had DCIS with invasive mammary carcinoma. The 9 cases with invasive mammary carcinoma in the surgical excision specimen (16%) and the 4 pure DCIS in surgical excision specimens that were ER/PR negative on core needle biopsy would need repeat ER/PR testing. The total unnecessary increased cost of core needle biopsy specimen testing of these 13 cases was $8148.92 ($140/patient for the 58 patients in the study). We found that ER/PR testing results impacted patient management in only 16/49 pure DCIS cases after surgical excision (33%), indicating that ER/PR testing costing $20,685.72 ($357/patient in the study) had been performed unnecessarily. PR testing could have been omitted in the 16 cases in which ER/PR results were used, which would have saved $5014.72, or $86.46 per patient. Extrapolating the increased cost of $583 per DCIS diagnosis on core needle biopsy to 60,000 new cases of DCIS in the United States each year, reflex core needle biopsy ER/PR testing unnecessarily increases costs by approximately $35 million. We recommend that ER/PR not be reflexively ordered on core needle biopsy specimens or surgical excision specimens containing DCIS, but instead that ER alone be performed on surgical excision specimens only when hormone therapy is a serious consideration after medical oncology consultation.

Separate cavity margin sampling at the time of initial breast lumpectomy significantly reduces the need for reexcisions.

In breast conservation therapy, the margin status of the specimen predicts local recurrence and determines the need for reexcision. Many surgeons now take, at the time of lumpectomy, multiple separate "cavity margins" (CM) (the entire wall of the residual cavity) as final margins that supersede the oriented lumpectomy margins (LMs). We studied the efficacy of this method in 126 patients (23 with ductal carcinoma in situ [DCIS] only and 103 with invasive carcinoma with or without DCIS) who had an oriented lumpectomy specimen and also had four to six additional CMs. The tumors were evaluated for the following: size, grade, LM status (distance of tumor from margin and, if involved, extent of involvement), vascular invasion, lymph node status, and presence or absence of extensive intraductal component. The additional CM specimens were evaluated for residual carcinoma (if any) and its distance from the inked true margins, and the results were correlated with the corresponding LMs. Only approximately 50% of patients (52 of 103) with histologically positive LMs (defined as carcinoma within 2 mm of the inked surface) had residual carcinoma in their CMs. Additional CM sampling rendered the overall final margin status histologically negative in 61 of 103 (59%) cases with histologically positive LMs, therefore significantly reducing the need for reexcision. Younger patient age, higher number of positive LMs, high tumor grade, and the presence of extensive intraductal component were predictive of residual carcinoma in CM specimens, whereas the distance of carcinoma from the inked surface and the extent of tumor involvement of histologically positive LMs were not. Because CM specimens taken from patients with histologically positive LMs usually lack tumor, we suspect that many positive LMs are likely false positives. Possible factors accounting for false-positive LMs include seepage of ink into crevices of the specimen promoted by excessive inking, tumor friability promoting displacement of tumor into ink, manipulation of specimens for radiographs, and retraction artifact.

Reflex estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 (ER/PR/Her2) analysis of breast cancers in needle core biopsy specimens dramatically increases health care costs.

ER/PR/Her2 are often reflexively assessed in all core needle biopsies (CNBXs) containing invasive mammary carcinoma (IMC) so that neoadjuvant therapy can be considered. ER/PR/Her2 can be heterogenous, and there is growing consensus that negative results for any of these markers in small CNBXs should be repeated in larger excision specimens (EXS). The frequency and added cost of repeat testing of EXS containing untreated IMC with negative ER/PR/Her2 CNBX results has not previously been studied. We reviewed 198 CNBXs containing IMC, which had reflex ER/PR/Her2 testing and for which there was an EXS for review. We determined the number of cases in which ER/PR/Her2 immunohistochemistry and Her2 fluorescence in situ hybridization were negative on CNBX. Twenty-seven (13.6%) patients received neoadjuvant chemotherapy, and 8 (4%) patients did not have IMC on follow-up EXS, so for them testing the CNBX was necessary. Of the remaining 163 IMCs, 17% were ER negative, and 26% were PR negative, whereas 85% were Her2 negative or equivocal. At our institution, ER/PR were repeated on slightly more than one half of ER/PR-negative tumors, whereas Her2 was repeated on less than one third of Her2-negative/equivocal tumors. Had all negative tests been repeated, the increased cost of testing both the CNBX and EXS would be $100,821. Extrapolating to 230,000 new cases of IMC in the United States each year, the increased cost of repeat testing of all negative ER/PR/Her2 CNBX results would be >$117 million dollars. Limiting reflex testing to ER would decrease the cost of repeat testing to $10 million dollars. We suggest that ER/PR/Her2 should not be reflexively performed on all CNBX specimens containing IMC but instead be routinely performed on EXS and only selectively on CNBX specimens if neoadjuvant chemotherapy is a serious consideration for that individual patient.

Treatment of complications after breast-conservation therapy.

Over the past 2 decades, breast-conservation therapy with lumpectomy and whole-breast radiotherapy has become a standard option for the majority of women with newly diagnosed breast cancer. Long-term local control is achieved in approximately 85% of patients, and the therapy is generally well tolerated. There can, however, be long-term effects on the breast and other nearby tissues that may range from asymptomatic findings on examination to severe, debilitating problems. Infection, fat necrosis, and severe musculoskeletal problems such as osteoradionecrosis or soft-tissue necrosis are uncommon, affecting less than 5% of patients. However, changes in range of motion, mild-to-moderate musculoskeletal pain, and arm and breast edema are much more common. As more women choose breast-conservation therapy for management of their breast cancer, physicians will encounter these problems, as well as in-breast tumor recurrence, with greater frequency. This review will focus on the incidence, contributing factors, and management of the late problems of infection, fat necrosis, musculoskeletal complications, and local recurrence following breast-conservation therapy.

Experience with reduction mammaplasty combined with breast conservation therapy in the treatment of breast cancer.

As the inclusion criteria for breast conservation therapy have continued to evolve to include lower quadrant tumors, very large breasts, and central tumors, the potential for significant disfigurement after breast conservation therapy has also increased. This has led some centers to develop coordinated oncology-plastic surgery approaches to ensure both adequate cancer resection and aesthetic appearance to the breasts. The authors applied this principle to a specific group of breast cancer patients--women with macromastia--who would benefit from reduction mammaplasty. Eleven women were identified from the senior author's (S.L.S.) reconstructive practice who underwent breast conservation therapy followed by breast reconfiguration and bilateral reduction mammaplasty. Preoperative brassiere sizes ranged from 34D to 46D. All women had immediate reduction after frozen sections from the lumpectomy/partial mastectomy margins were determined to be negative. A total of 22 reduction mammaplasties were performed (eight free-nipple grafts, five inferior pedicle flaps, seven superomedial pedicle flaps, and two superolateral flaps) and an average of 1085 g was removed per breast. All patients underwent radiation therapy postoperatively. There were eight minor complications in six patients (one hematoma, one keloid, one radiation burn, two cases of nipple hypopigmentation, and three cases of fat necrosis). After an average of 24 months' follow-up, there were no local recurrences and one death from distant metastasis. Seven of the 11 patients were available and agreed to rate their aesthetic satisfaction on the basis of a scale from 1 to 4, with 4 being the best. The mean satisfaction score was 3.3. Aesthetic outcomes before radiation therapy and after radiation therapy were evaluated by a panel of plastic surgery residents blinded to the purpose of the study. Using a scale of 1 to 4, the aesthetic mean before radiation therapy was 2.9 and the aesthetic mean after radiation therapy was 3.03. By combining breast conservation therapy with breast reconfiguration or reduction in large-breasted women, multiple benefits are derived. Larger segmental or partial mastectomies can be performed without disfigurement risk, ensuring adequate surgical margins. Immediate reconfiguration of the breast with reduction of the contralateral side creates symmetric, aesthetically pleasing breasts; allows contralateral breast tissue to be evaluated; and spares women from undergoing a second operative procedure. Such a coordinated program gives women an important boost, both physically and psychologically, during management of their breast cancer.

Borderline atypical ductal hyperplasia/low-grade ductal carcinoma in situ on breast needle core biopsy should be managed conservatively.

The differential diagnosis of low-nuclear grade intraductal epithelial proliferations of the breast includes atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). This distinction can be difficult on core needle biopsy (CNB) but can have significant clinical ramifications. We examined the clinical course of patients diagnosed on CNB with borderline ADH/DCIS lesions [marked ADH (MADH)] at our institution. A total of 74 patients were diagnosed with MADH on CNB and underwent an excisional biopsy (EB). The majority of these CNBs reviewed at outside hospitals had been classified as DCIS. Twenty patients (27%) had benign findings or lobular neoplasia in their EB, 18 (24%) had ADH, 33 (45%) had DCIS, and 3 (4%) had DCIS and invasive ductal carcinoma (IDC). Among the 38 patients who were not diagnosed with DCIS or IDC on EB, no patient underwent further surgery or radiation postoperatively. Thirty-seven of these 38 patients had no recurrences, whereas 1 patient developed a "recurrence" that on our review was likely residual localized MADH. The mean follow-up for these patients was 54 months. Of the 36 patients diagnosed with DCIS or IDC on EB, <20% required mastectomy. On review, MADH involving an intermediate-sized duct on CNB and the amount of residual lesion on imaging was significantly associated with DCIS or IDC on EB. Conversely, MADH involving columnar cell lesions and the presence of calcification on CNB were significantly associated with benign pathology on EB. In conclusion, our study provides preliminary data that justify a conservative approach to borderline ADH/DCIS lesions on CNB: that is, diagnose as MADH and treat by conservative excision.

Biomarker modulation following short-term vorinostat in women with newly diagnosed primary breast cancer.

PURPOSE: Agents that target the epigenome show activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell-cycle arrest, apoptosis, and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly diagnosed invasive disease who received vorinostat and those who did not. EXPERIMENTAL DESIGN: Tumor specimens were collected from 25 women who received up to 6 doses of oral vorinostat 300 mg twice daily and from 25 untreated controls in a nonrandomized study. Candidate gene expression was analyzed by reverse transcription PCR (RT-PCR) using the Oncotype DX 21-gene assay, and by immunohistochemistry for Ki-67 and cleaved caspase-3. Matched samples from treated women were analyzed for gene methylation by quantitative multiplex methylation-specific PCR (QM-MSP). Wilcoxon nonparametric tests were used to compare changes in quantitative gene expression levels pre- and post-vorinostat with changes in expression in untreated controls, and changes in gene methylation between pre- and post-vorinostat samples. RESULTS: Vorinostat was well tolerated and there were no study-related delays in treatment. Compared with untreated controls, there were statistically significant decreases in the expression of proliferation-associated genes Ki-67 (P = 0.003), STK15 (P = 0.005), and Cyclin B1 (P = 0.03) following vorinostat, but not in other genes by the Oncotype DX assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed. CONCLUSIONS: Short-term vorinostat administration is associated with a significant decrease in expression of proliferation-associated genes in untreated breast cancers. This demonstration of biologic activity supports investigation of vorinostat in combination with other agents for the management of breast cancer.