Lisa Jacobs

Positive Margins: The Challenge Continues for Breast Surgeons

As breast cancer treatment has progressed to offering breast preservation to the majority of patients, a new challenge has arisen. That challenge is adequate margins on the partial mastectomy specimen. The literature reports positive margins in 20–70% of patients, resulting in additional surgery. While the consequences of that additional surgery probably do not affect survival from breast cancer, they do potentially have an affect on cosmesis, wound infection risk, and the confidence that the patient has with the surgeon wondering “why didn’t you get it all?” The article “Predictors of Re-excision Among Women Undergoing Breast Conserving Surgery for Cancer” by Waljee et al.1 attempts to identify the factors that increase the risk of a positive margin. This avenue of research is important in clinical management of breast cancer, allowing surgeons to more intelligently counsel patients regarding risk of re-excision. The authors identified several factors that predict a higher rate of positive margins. Smaller breast size, surgical biopsy for diagnosis, use of adjuvant chemotherapy, and lobular histology all predicted a higher rate of positive margins. Another study published in the Annals of Surgical Oncology studied the same topic and agreed that method of biopsy and lobular histology result in higher positive margin rates.2 A large prospective study reported from the University of Louisville Breast Cancer Sentinel Lymph Node Study included 2658 patients treated with lumpectomy and evaluated factors that resulted in positive margins. They found that larger tumor size and lobular histology both resulted in higher positive margin rates, but that method of biopsy had no impact.3 While these studies agree on many risk factors for positive margins, unfortunately, these factors, with the exception of biopsy method, cannot be modified. Few women would agree to undergo mastectomy instead of lumpectomy because of a prediction of positive margins. Because the factors predicting higher re-excision rates are not modifiable, this line of research can only result in providing additional knowledge but cannot result in changes in practice. Efforts to investigate mechanisms that reduce the rate of positive margins have much greater potential to impact treatment. A number of studies have investigated surgical interventions that may reduce the rate of positive margins. Many have investigated intraoperative pathologic assessment as a mechanism to identify positive margins at the time of surgery so that re-excision can be accomplished in the same setting. These have focused primarily on touch imprint cytology, frozen section, and gross examination. Muttalib et al. evaluated intraoperative imprint and scrape cytology to assess margins. While the authors recommend adoption of the technique, the positive margin rate reported in the study remained at 22% with use of the technique.4 Intraoperative assessment of gross margins has been reported to result in a final margin positive rate of 25%.5 Investigators at MD Anderson Cancer Center evaluated a combination of intraoperative gross margin assessment, specimen radiography, and in some cases frozen section with a final positive margin rate of 20% using these methods.6 Others have evaluated intraoperative methods of tumor localization and their impact on positive margins. Tafra et al. completed a randomized study comparing cryoassisted localization with wire localization and demonstrated no difference in positive margins.7 Radioguided occult lesion localization was compared with wire localization by Nadeem et al., who demonstrated a positive margin rate of 83% and 57%, respectively.8 Other techniques have focused on volume of excision with oncoplastic techniques allowing for larger margin excisions while maintaining the cosmetic appearance of the breast. While these techniques in intraoperative assessment and changes in surgical technique may reduce the rate of positive margins, they have not solved the problem. Other possible mechanisms that are currently unproven but that may result in lower re-excision rates include improved preoperative imaging to better establish extent of disease and increased use of neoadjuvant chemotherapy. Studies evaluating the utility of magnetic resonance imaging (MRI) find an increased sensitivity for detection of multicentric and multifocal disease. Identifying this situation preoperatively will result in better patient selection for attempted partial mastectomy. We have also found MRI helpful in defining the extent of disease in the breast more accurately identifying the extent of resection required. Improved neoadjuvant chemotherapy regimens have resulted in patients with significantly smaller tumors and in some cases patients with a pathologic complete response. Neoadjuvant chemotherapy regimens that include Herceptin report a pathologic complete response rate of up to 60%.9 Of course this would reduce those patients with positive margins by reducing the number of patients with evidence of disease in the breast and also by reducing the tumor volume. In fact, the study by Waljee reported a lower positive margin rate with neoadjuvant chemotherapy.1 While many of these techniques may reduce the rate of positive margins, the best reports result in at least 20% of the patients returning to the operating room for re-excision. This rate remains too high despite our best efforts. New innovative surgical techniques, methods of intraoperative margin assessment, imaging for patient selection, and improved neoadjuvant chemotherapies are needed to prevent one in five patients from returning to the operating room.

Differentiation of colonic metaplasia from adenocarcinoma of urinary bladder

Colonic metaplasia and primary bladder adenocarcinoma are relatively uncommon entities that can have similar gross clinical appearances. Examples of colonic metaplasia histologically mimicking cancer have only rarely been reported. We retrospectively analyzed 38 cases of cystitis glandularis (18 cases of colonic metaplasia), 12 cases of adenocarcinoma of urinary bladder (two well-differentiated, WDA), and one in situ adenocarcinoma from the surgical pathology files of Johns Hopkins Hospital. Nine patients with colonic metaplasia had widespread lesions. Two showed superficial muscularis propria involvement, mimicking adenocarcinoma; one of these cases had been diagnosed as infiltrating WDA at both an academic center and a community hospital. Dissecting mucin pools were focally seen in four cases of widespread colonic metaplasia, also mimicking cancer. One of the nine cases showed minimal cytological atypia, but no cases showed mitoses or signet ring cells. Distinguishing WDA from colonic metaplasia was the finding in WDA of infiltrative architectural pattern (two of two), extensive muscle invasion (two of two), moderate anaplasia (one of two), mitotic figures (two of two), and extensive mucinous pools (one of two). The diagnosis of adenocarcinoma in situ was based on anaplasia. Clinically, colonic metaplasia may resemble cancer. Histologically, colonic metaplasia may mimic cancer based on extensive involvement of the lamina propria, focal mucinous pools, focal muscularis propria involvement, focal mild cytological atypia, and rare mitoses. Despite overlapping features with colonic metaplasia, the diagnosis of WDA is based on the greater degree and extent of these atypical findings in cancer.

Rectal cancer: the sphincter-sparing approach

There is considerable skepticism regarding sphincter-preserving surgery for rectal cancer, and 40% to 60% APR rates are reported in many prospective studies. Despite radical surgery, 20% positive margin rates are frequently reported. Rectal carcinoma responds to preoperative chemoradiation therapy with a 10% to 15% pathologic complete response rate. Preoperative therapy offers an opportunity to reduce the positive margin rate and to reduce the APR rate. Because there is significant tumor regression with preoperative therapy, distal margins of less 1 cm are acceptable and do not result in suture line recurrence. APR rate of less than 10% is feasible and better chemotherapy with radiation therapy will reduce the APR to less than 5%.

Primary Breast Sarcoma

Primary breast sarcomas are rare breast malignancies. This article describes the clinical management of the disease, including the controversies surrounding the pathologic classification, role of surgery, and adjuvant therapy.

African American Women Who Receive Primary Anthracycline- and Taxane-Based Chemotherapy for Triple-Negative Breast Cancer Suffer Worse Outcomes Compared With White Women

TO THE EDITOR: We read with great interest the manuscript by Dawood et al from the M. D. Anderson Cancer Center (MDACC; Houston, TX) entitled, “Triple Receptor–Negative Breast Cancer: The Effect of Race on Response to Primary Systemic Treatment and Survival Outcomes.” We have also recently evaluated a data set of women with triple receptor–negative breast cancer who received primary systemic therapy (PST) at our institution and report our observations below. Breast cancer is a heterogeneous disease composed of a number of recognized biologic and pathologic subtypes. The so called “triple receptor–negative breast cancer,” used to describe all tumors that are estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor 2–negative, may include basal-like and non– basal-like tumors. Chemotherapy is the only systemic treatment available for women with primary triple receptor–negative breast cancer to improve long-term outcomes. Triple receptor–negative breast cancer is more prevalent among premenopausal African American women and is associated with a shorter disease-free interval and overall survival than white women. This disparity has been often attributed to lack of access to healthcare, poor follow-up, low socioeconomic status, body mass index, and possibly lower doses of adjuvant therapy. Dawood et al have previously reported that African American women with metastatic breast cancer are at greater risk of death compared with white women. African American women with triple receptor–negative breast cancer often present with a stage II or III breast cancer and may be recommended PST. Although PST does not improve disease-free survival or overall survival, it may enhance breast conservation and provide prognostic information to individual women. Women with poor response to PST and a large residual disease are more likely to suffer a recurrence and die of their disease compared with women with a pathological complete response (pCR). Based on available evidence and anecdotal observations, we hypothesized that African American women with triple receptor– negative breast cancers have worse outcomes in part because of resistance to standard chemotherapy. To test our hypothesis, we compared pCR rate, recurrence-free and overall survival, in African American versus white and other women with triple receptor–negative breast cancer who received preoperative anthracyclineand/or taxane-based therapy. In 2002, members of the multidisciplinary breast cancer program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University Hospital (Baltimore, MD) developed an algorithm for PST management used by the clinicians from all specialties, which led to uniform identification, staging, and treatment criteria. Briefly, women with a clinical stage II or III breast cancer appropriate for PST based on International Consensus Recommendations had nodal evaluation by a fine-needle aspiration or sentinel node mapping before initiating chemotherapy. The breast cancer program screens and collects demographics and key medical characteristics on all new patients to the medical oncology clinic. All patients with a clinical stage II or III breast cancer at the time of initial consultation who received PST are included in the database. Approximately 2 to 4 weeks following PST, women undergo breast-conserving surgery or a mastectomy at the Johns Hopkins at the discretion of the treating surgeon and patient preference. Women with a positive axillary lymph node before chemotherapy undergo axillary lymph node dissection at time of definitive surgery. We reviewed the breast cancer PST database from May 2002 to December 2007. Eligible subjects for the investigation included women with histologically confirmed, estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor 2–negative, clinical stage II or III, invasive breast cancer who received chemotherapy with doxorubicin and cyclophosphamide, with or without a taxane before or after the doxorubicin and cyclophosphamide combination. The Johns Hopkins Medicine institutional review board provided an exemption for this retrospective review. We studied patient and tumor characteristics including age, race, family history, menopausal status, initial clinical stage, initial clinical tumor size and nodal status. Study end points included pCR (no residual invasive cancer in the breast and lymph nodes), recurrencefree survival, and overall survival in African American versus white/ other women. Differences in patient and tumor characteristics across race were compared with Fisher’s exact test, exact 2 test, or Wilcoxon rank sum test, where appropriate. Survival outcomes including recurrence-free survival and overall survival were analyzed using the Kaplan-Meier method and compared between race groups by the log-rank test. We identified 38 women that met the predefined criteria; 15 were African American, 23 were white or other race (Table 1). Consistent with the literature, African American women were more likely to be younger than 50 years of age and be preor perimenopausal at the time of initial diagnosis. There was no statistically significant difference between initial clinical stage and type of chemotherapy administered to the groups. Following therapy, 13% of the African American women had a pCR compared with 52% in white/other women (P .034). Fewer white/other women had a stage III residual pathological stage compared with African American women (12% and 53%, respectively). With a median follow-up of 2.1 years (range, 0.6 to 6.5 years), Kaplan-Meier curves indicate a trend for shorter recurrence-free survival (P .045) and overall survival (P .028) for African American women compared with white/other women (Fig 1). The trends remained similar after controlling for patient and tumor characteristics. JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E VOLUME 27 NUMBER 22 AUGUST 1 2009

A PIK3CA mutation detected in plasma from a patient with synchronous primary breast and lung cancers

Digital polymerase chain reaction is a new technology that enables detection and quantification of cancer DNA molecules from peripheral blood. Using this technique, we identified mutant PIK3CA DNA in circulating ptDNA (plasma tumor DNA) from a patient with concurrent early stage breast cancer and non-small cell lung cancer. The patient underwent successful resection of both her breast and lung cancers, and using standard Sanger sequencing the breast cancer was shown to harbor the identical PIK3CA mutation identified in peripheral blood. This case report highlights potential applications and concerns that can arise with the use of ptDNA in clinical oncology practice.

The audit process and how to ensure a successful audit.

Clinical trials are valuable in both advancing the scientific knowledge of surgical oncology and defining the very best care for patients afflicted by malignancies. As an obligation to both the scientific community and the general public, the cooperative audit programs and the CTMB collaborate to ensure that the conduct of clinical trials are meticulous and the data are validated. However, audit programs should be viewed not merely as a surveillance mechanism. It serves as a stimulus for performance improvement by providing opportunities for peer-review and education.

Translational Research in Surgical Disease

OBJECTIVE To review cutting-edge, novel, implemented and potential translational research and to provide a glimpse into rich, innovative, and brilliant approaches to everyday surgical problems. DATA SOURCES Scientific literature and unpublished results. STUDY SELECTION Articles reviewed were chosen based on innovation and application to surgical diseases. DATA EXTRACTION Each section was written by a surgeon familiar with cutting-edge and novel research in their field of expertise and interest. DATA SYNTHESIS Articles that met criteria were summarized in the manuscript. CONCLUSIONS Multiple avenues have been used for the discovery of improved means of diagnosis, treatment, and overall management of patients with surgical diseases. These avenues have incorporated the use of genomics, electrical impedence, statistical and mathematical modeling, and immunology.

Abstract A22: Association of breast cancer risk and concentrations of tissue estrogens to single strand breaks in DNA

Introduction: Single-strand breaks (SSB) in DNA are discontinuities in one strand of the DNA and are usually accompanied by loss of a single base and by damaged 5- or 3-termini at the site of the break. If not repaired rapidly or appropriately, chromosomal SSBs pose a serious threat to genetic stability and cancer development. We hypothesize that if the presence of single strand DNA breaks can be quantified directly, it will provide a means of detecting a process that puts cells at high risk of developing cancer. The association between a quantitative measure of SSB and other measures of breast cancer risk was determined. Subjects: 206 postmenopausal and 99 premenopausal, healthy women with intact, healthy bilateral breasts, without implants or history of radiation, willing to undergo a random fine-needle aspiration (rFNA) of the breast within 3.5 months of a normal mammogram were recruited to the study. Exclusions: use of tamoxifen, raloxifene, or aromatase inhibitor within 2 years of participation or oral contraceptives or other hormone treatments within 3 months of study enrollment. Participants completed personal and medical history questionnaires. Blood for hormone levels and random fine needle aspirates of the breast (rFNA) were collected following a breast exam. Methods: rFNA of the breast of women at unspecified risks for breast cancer were analyzed for SSB by a nick translation procedure. SSB levels digital two-dimensional breast density of the entire breast (PBD), mRNA of genes associated with DNA damage, and breast steroid concentrations by a LC/MS/MS procedure. Results: Based on the cpm in the purified sample, the specific activity of the 3H-dCTP, and quantity of DNA in the sample, the incorporation of 3H-dCTP ranged from 0.03 to 8.59 pmol/µg DNA. The β-coefficients for the relationships between SSB and measures of breast cancer risk were determined by a multiple regression procedure. PBD adjusted for age was associated with SSB in postmenopausal women (P = 0.007) but was not associated with SSB in premenopausal women. Further adjustment for BMI reduced the PBD relationship to SSB by 35% but adjustment for BMI. APEX1 was not significantly associated with SSB. XRCC1 mRNA was negatively associated with SSB in premenopausal women (p = 0.016), and was not altered by adjustment for age. The antioxidant functions NRF-1 and SOD2 were both significantly negatively associated with SSBs, P = 0.001 and 0.045, respectively, and both were decreased by less than 5% after adjustment for age. Breast tissue concentrations of 4-hydroxyestradiol exceeded those of estradiol, were correlated with tissue estradiol, and were significantly (P = 0.011) negatively related to SSB levels. Breast tissue concentrations of estradiol, estrone, 4-hydroxyestrone, and androstenedione were not significantly related to SSB. Conclusions: The most likely mechanism by which 4-OHE2 or 2-OHE1 could protect against formation of SSBs in the breast is by their antioxidative properties. 4-OHE2 and other catechol estrogens are capable of undergoing redox reactions, cycling between the catechol structure, semiquinone radical, and o-quinone. They are also capable of forming metal complexes, sequestering metals, preventing them from undergoing redox reactions. In addition, 4-OHE2 has a binding affinity relative to that of estradiol of 1.51; that of 2-OHE1 is 1.02 Therefore, the catechol estrogens have activity similar to or greater than that of estradiol in terms of activation of NRF-1 and Mn SOD, both of which were elevated in association with lower SSB levels. We conclude that SSBs measured by the nick translation procedure are associated with, but not redundant with, measures of breast cancer risk and with deficiencies of both DNA damage responses and antioxidant mechanisms. Concentrations of 4-hydroxyestradiol in breast tissue may serve an antioxidant function and may be protective. Citation Format: Mathavi Sahadevan, Oukseub Lee, Miguel Muzzio, Belinda Phan, Lisa Jacobs, Nagi Khouri, Jun Wang, Hong Hu, Vered Stearns, Robert T. Chatterton. Association of breast cancer risk and concentrations of tissue estrogens to single strand breaks in DNA. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A22.

The relationship of single-strand breaks in DNA to breast cancer risk and to tissue concentrations of oestrogens

Abstract Context: Clinical study of breast cancer patients in Chicago, IL, USA. Objective: Ascertain the utility of measurements of single-strand breaks (SSB) in DNA for assessment of breast cancer risk. Methods: Fine-needle aspirates of the breast, SSB by nick translation, percent breast density (PBD), Gail model risk, cumulative methylation index (CMI), enzymes of DNA repair and tissue antioxidants. Results: DNA repair enzymes and 4-hydroxyestradiol were negatively associated with SSB; CMI and PBD were positively associated. Conclusions: Quantitative measurement of SSBs by this procedure indicates the relative number of SSBs and is related to promoter methylation, antioxidant availability and percent breast density.