Impact of Oncotype DX on treatment decisions in ER-positive, node-negative breast cancer with histologic correlation.

Oncotype DX, a gene-expression profiling assay, provides stratification of patients with estrogen-receptor positive, lymph-node-negative early breast cancer into risk groups based on recurrence score, which are associated with distant recurrence and response to chemotherapy. This study aims to determine whether Oncotype DX influences clinicians' treatment decisions, and whether assay results correlate with histologic assessment. Fifty patients with estrogen-receptor positive, node-negative early breast cancer analyzed by Oncotype DX and operated on by two breast surgeons were included. To assess effect on treatment decisions, clinical vignettes were created by retrospective chart review. Physicians were then presented with the clinical vignettes and instructed to make a treatment decisions (i.e., hormone therapy alone versus hormone therapy combined with chemotherapy) both before and after knowledge of the recurrence score. To assess correlation with histologic assessment, a prospective, blinded review of tumor slides was performed by two pathologists. Based on this review, tumors were placed into low, intermediate and high risk groups for comparison with Oncotype DX assay results. Treatment decisions were changed based on Oncotype DX results in 36 and 18% of cases by breast surgeons and medical oncologists, respectively. All tumors categorized as high risk by Oncotype DX were categorized as high risk based on histologic assessment, and 96% of cases categorized as low risk by recurrence score were categorized as low or intermediate risk by histologic assessment. Oncotype DX significantly influences management of estrogen-receptor positive, lymph-node-negative early breast cancer. Further studies are needed to assess association of histologic categorization to assay results.

Adjuvant therapy in stage I carcinoma of the breast: the influence of multigene analyses and molecular phenotyping.

BACKGROUND: Breast Health International and the Kimmel Cancer Center of Thomas Jefferson University cosponsored a consensus conference that included an international group of experts. METHODS: Since the adoption of adjuvant chemotherapy for stage I, lymph node-negative breast cancers in 1988, investigators have tried to "fine-tune" the treatment criteria. At this consensus conference, the group debated recommendations for adjuvant hormone and cytotoxic chemotherapy in stage I breast cancers. RESULTS: Discussions during the conference addressed issues of adjuvant therapy for stage I breast cancer and the influence of multigene analyses and molecular phenotyping. The panelists discussed various demographic, morphologic, biologic, and genetic factors expressed by individual tumors and their influence on treatment decisions. CONCLUSIONS: The panel tried to create guidelines for the consideration of adjuvant treatment of these patients, including both hormone and cytotoxic regimens. They also encouraged further research into the molecular analysis of breast cancers and the introduction of clinical trials based on current data, although they concluded that it is too early to add any of those analyses into the decision-making algorithms of recommendations for the treatment of stage I breast cancer.

Progression of ductal carcinoma in situ to invasive breast cancer is associated with gene expression programs of EMT and myoepithelia.

Ductal carcinoma in situ (DCIS) is a precursor lesion that can gives rise to invasive breast cancer (IBC). It has been proposed that both the nature of the lesion and the tumor microenvironment play key roles in progression to IBC. Here, laser capture microdissected tissue from pure DCIS and pure IBC were employed to define key gene expression profiles in either the epithelial or stromal compartment associated with disease progression. Each tissue had distinct gene expression profiles, and a DCIS/IBC classifier accurately distinguished DCIS versus IBC in multiple independent data sets. However, contrary to other studies that profiled DCIS associated with invasive disease, we found that the most significant alterations in gene expression were observed in the epithelial compartment rather than in the stroma. In particular, genes associated with epithelial-to-mesenchymal transition and myoepithelial cell-specific genes were enriched in invasive cancer relative to pure DCIS. Such alterations in transcript levels were associated with all subtypes of breast cancer, but were particularly indicative of poor outcome in ER-negative breast cancer. Together, these studies indicate that lesion-specific differences in gene expression associated with invasive phenotype are particularly relevant in the progression of DCIS to invasive breast cancer.

Association of RB/p16-pathway perturbations with DCIS recurrence: dependence on tumor versus tissue microenvironment.

The prevalence of ductal carcinoma in situ (DCIS) diagnoses has significantly increased as a result of active radiographic screening. Surgical resection and hormone and radiation therapies are effective treatments, but not all DCIS will progress to invasive breast cancer. Therefore, markers are needed to define tumors at low risk of recurrence and progression that can be treated by surgery alone rather than by adjuvant therapies. Initial analyses indicate that retinoblastoma (RB)-pathway perturbations occur at high frequency in DCIS and mirror the molecular alterations observed in invasive breast cancer. Particularly, the elevated expression of p16ink4a in DCIS was associated with loss of RB function and estrogen receptor-negative biology. Furthermore, high expression of p16ink4a in conjunction with Ki-67 was associated with increased risk of DCIS recurrence and progression to invasive disease in multivariate analyses. These data are consistent with a functional role for RB in modulating the invasive behavior of mammary epithelial cells. The tissue microenvironment is particularly relevant to the behavior of DCIS, and, surprisingly, elevated expression of p16ink4a in nonproliferative stroma was observed in a substantial fraction of cases. In this tissue compartment, p16ink4a expression was strongly associated with disease recurrence, independent of standard histopathologic features. Together, the data herein describe dual aspects of RB-pathway biology that are associated with disease recurrence through the epithelial or stromal compartment of DCIS.

Adjuvant therapy in stage I carcinoma of the breast: the influence of multigene analyses and molecular phenotyping.

A consensus conference was held in order to provide guidelines for the use of adjuvant therapy in patients with Stage I carcinoma of the breast, using traditional information, such as tumor size, microscopic character, Nottingham index, patient age and co-morbidities, but also incorporating steroid hormone and Her-2-neu data as well as other immunohistochemical markers. The role of the genetic analysis of breast cancer and proprietary gene prognostic signatures was discussed, along with the molecular profiling of breast cancers into several groups that may predict prognosis. These molecular data are not currently sufficiently mature to make them part of decision making algorithms of recommendations for the treatment of individual patients.

Prognostic markers and long-term outcomes in ductal carcinoma in situ of the breast treated with excision alone.

BACKGROUND: Increased use of breast cancer screening has led to an increase in the number of diagnosed cases of ductal carcinoma in situ (DCIS). However, there is no definite way to predict progression or recurrence of DCIS. We analyzed the significance of biological markers and tumor characteristics in predicting recurrence in a large series of DCIS patients with long-term follow-up treated with breast conservation surgery (BCS) alone. METHODS: Clinical and pathological data were analyzed for 141 patients who underwent BCS for DCIS. All had negative surgical margins. Using local disease recurrence as an endpoint, we sought to determine the prognostic significance of several histopathological characteristics (tumor size, presence of necrosis, and subtype) and biological markers (estrogen receptor, progesterone receptor, and Her-2/neu.) RESULTS: At a median follow-up of 122 months (maximum follow-up, 294 months), 60 recurrences occurred, with a median time to recurrence of 191 months. On multivariate analysis, Her-2 positivity (3+) was found to be significantly associated with reduced time to tumor recurrence (P = .028). Tumor size and higher grade were marginally statistically significant (P = .099, P = .070). Neither necrosis nor tumor pathological characteristics were found to be significantly related to time to disease recurrence. CONCLUSIONS: Our results suggested that status of Her-2/neu, larger tumor size, and higher nuclear grade were significantly correlated with time to tumor recurrence in patients treated with BCS alone. Using logistical analyses, no significant correlation was found between tumor pathological characteristics and disease recurrence.

Increased SIAH expression predicts ductal carcinoma in situ (DCIS) progression to invasive carcinoma.

Hyperactivated HER2/Neu/EGFR/RAS signaling is a major growth-promoting pathway known to drive cellular transformation and oncogenesis in breast cancers. HER2 amplification is detected in ~20% of all human breast cancer and is quite prevalent (up to 49%) in ductal carcinoma in situ (DCIS). The E3 ubiquitin ligase SIAH is considered a key downstream "gatekeeper" required for proper HER2/EGFR/RAS signal transduction. Formalin-fixed, paraffin-embedded resection specimens from 65 patients with DCIS treated with wide excision only were stained with an anti-SIAH antibody, and the percentage of tumor and normal adjacent tissue cells positive for SIAH nuclear staining were recorded. Statistical analysis was performed comparing SIAH staining in tumor cells to disease recurrence, histologic type, necrosis, hormone receptor status, and Her2/neu status, as well as nuclear grade. Correlation of SIAH expression in tumor cells with SIAH expression in normal adjacent tissue and age was also examined. Expression levels of SIAH in tumor cells was significantly higher in specimens from patients with recurrence (median = 19%) as compared to patients without recurrence (7%) (P < 0.001). There was also significantly increased SIAH expression in tumors with more aggressive features including comedo morphology (13.5% in comedo vs. 7% in other histologic types, P = 0.014). No significant association was observed between SIAH expression and estrogen receptor, progesterone receptor, and Her2/neu status. There was a significant correlation between SIAH expression in tumors and normal adjacent tissue (Spearman correlation = 0.58, P < 0.001) as well as between SIAH expression in normal adjacent tissue and patient age (Spearman correlation = -0.59, P < 0.001). No significant correlation was identified between patient age and SIAH expression in tumors (Spearman correlation = -0.23, P = 0.067). In conclusion, SIAH may represent a useful prognostic biomarker that predicts DCIS progression to invasive breast cancer.

Molecular grading of ductal carcinoma in situ of the breast.

PURPOSE: Increased incidence of ductal carcinoma in situ (DCIS) associated with mammographic screening for breast cancer has emphasized the challenges of managing this condition. The aim of this study was to identify informative clinical indicators of DCIS biology by molecular profiling. EXPERIMENTAL DESIGN: Areas of in situ carcinoma, atypical ductal hyperplasia, and benign epithelium were microdissected from 46 invasive breast cancers. Oligonucleotide probes showing differential expression between DCIS associated with grade 1 and 3 invasive cancer were identified by microarray-based gene expression profiling. Expression at these probes was used to define a "molecular grade" subcategorization of all samples. The genomic basis of molecular grade was examined by array-based comparative genomic hybridization. Clinical course was examined in a cohort of 134 patients with DCIS treated by surgery alone. RESULTS: DCIS samples were designated as low or high molecular grade based on expression at 173 probes. The low molecular grade subgroup included low (n = 10) and intermediate (n = 11) nuclear grade DCIS as well as all samples of atypical ductal hyperplasia (n = 4) and benign epithelium (n = 7). The high molecular grade subgroup included DCIS of intermediate (n = 7) and high (n = 19) nuclear grade. The character and degree of genomic aberration were distinct between molecular grade subgroups. A classification tree model including nuclear grade and Ki67 score accurately predicted molecular grade for 95.7% of samples. In an independent cohort, this showed a pattern of rapid disease recurrence for high molecular grade DCIS. CONCLUSIONS: Molecular profiling indicates a binary grading scheme for DCIS. This practical approach has potential to improve clinical evaluation of DCIS.

Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007.

A consensus conference including thirty experts was held in April, 2007, to discuss risk factors for breast cancer and their management. Four categories of risk were outlined, from breast cancer "average" through "very high" risk, the latter including individuals with high penetrance BRCA1/2 gene mutations. Guidelines for management of patients in each of these categories were discussed, with the major portion of the conference being devoted to individuals with BRCA1/2 mutations. Prevalence of these mutations in the general populations was estimated to be 1 in 250-500 individuals, with an increased prevalence in Ashkenazic Jews and other founder groups. Risk reduction strategies for these individuals include surveillance, with or without chemoprevention drugs, or surgical procedures to remove the organs at risk, i.e., bilateral mastectomy and/or bilateral salpingo-oophorectomy. These risk reduction strategies were evaluated fully, and recommendations were made for the care of patients in each of the risk categories. These guidelines for patient care were approved by the entire group of experts.

Primary mucosa-associated lymphoid tissue lymphoma of the breast.

Mucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal indolent lymphoma with histopatholigic features similar to those of marginal zone B-cell lymphomas. Primary breast MALT lymphomas were first described by Lamovec and Jancar as a low-grade B-cell lymphoma in 1987. Herein, a case is presented of a patient with primary MALT lymphoma of the breast. Issues in diagnosis and breast-conservation treatment, as it pertains to primary MALT lymphoma of the breast, will be discussed.

Breast conservation after neoadjuvant chemotherapy for stage II carcinoma of the breast.

BACKGROUND: Neoadjuvant chemotherapy has become the standard treatment for stage III breast cancer. Gratifying results in these patients prompted this prospective, nonrandomized study of neoadjuvant chemotherapy in stage II breast cancer. This study presents our experience with neoadjuvant chemotherapy in 127 patients with stage II carcinoma of the breast. STUDY DESIGN: Patients with stages IIA (T > 3.0 cm) and IIB carcinoma were considered for this study and underwent treatment with cyclic chemotherapy until a plateau of response was achieved. Responders underwent breast conservation or mastectomy according to conventional assessment. Chemotherapy was continued in the adjuvant setting. Survival data were compared with historic controls. RESULTS: Between 1981 and 2001, 127 women between the ages of 22 and 80 years (mean age 52, median age 50), with stage II breast cancer were enrolled, with median followup of 60 months. One hundred twenty-two patients (96.1%) responded to chemotherapy. Of this group, 35 (29.2%) experienced complete pathologic responses or had only microscopic foci of disease after treatment. Sixty-two patients (52.5%) had negative lymph nodes at the time of the operation; 28 of these patients were previously considered N-1 clinically. Seventy-six patients (62%) underwent breast conservation. Overall survivals at 5 years for stage IIA and IIB disease were 94.7% and 88%, respectively. Disease-free survival at 5 years was 85.2% for stage IIA patients and 69.1% for stage IIB patients. CONCLUSIONS: Neoadjuvant chemotherapy can be effectively applied to patients with stage II disease, and breast conservation becomes feasible in the majority of patients. When compared with historic controls, the current study suggests a statistically significant overall survival advantage (p < 0.007) at 5 years.

Influence of radiation dose on positive surgical margins in women undergoing breast conservation therapy.

PURPOSE: Positive surgical margins adversely influence local tumor control in breast conservation therapy (BCT). However, reports have conflicted regarding whether an increased radiation dose can overcome this poor prognostic factor. In this study, we evaluated the influence of an increased radiation dose on tumor control in women with positive surgical margins undergoing BCT. METHODS AND MATERIALS: Between 1978 and 1994, 733 women with pathologic Stage I-II breast cancer and known surgical margin status were treated at Thomas Jefferson University Hospital with BCT. Of these 733 patients, 641 women had a minimal tumor bed dose of 60 Gy and had documentation of their margin status; 509 had negative surgical margins, and 132 had positive surgical margins before definitive radiotherapy. Complete gross excision of the tumor and axillary lymph node sampling was obtained in all patients. The median radiation dose to the primary site was 65.0 Gy (range 60-76). Of the women with positive margins (n = 132), the influence of higher doses of radiotherapy was evaluated. The median follow-up time was 52 months. RESULTS: The local tumor control rate for patients with negative margins at 5 and 10 years was 94% and 88%, respectively, compared with 85% and 67%, respectively, for those women with positive margins (p = 0.001). The disease-free survival rate for the negative margin group at 5 and 10 years was 91% and 82%, respectively, compared with 76% and 71%, respectively, for the positive margin group (p = 0.001). The overall survival rate of women with negative margins at 5 and 10 years was 95% and 90%, respectively. By comparison, for women with positive surgical margins, the overall survival rate at 5 and 10 years was 86% and 79%, respectively (p = 0.008). A comparison of the positive and negative margin groups revealed that an increased radiation dose (whether entered as a dichotomous or a continuous variable) >65.0 Gy did not improve local tumor control (p = 0.776). On Cox multivariate analysis, margin status and menopausal status had prognostic significance for local tumor control and DFS. CONCLUSION: Patients with positive surgical margins have a higher risk of local tumor recurrence and worse survival when undergoing BCT. Higher doses of radiation are unable to provide an adequate level of local control in patients with positive margins.

Proceedings of the consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast April 19 to 22, 2001, Philadelphia, Pennsylvania.

A consensus conference on the role of sentinel node biopsy in breast cancer was held in Philadelphia in April 2001. The participants included many highly respected American and European investigators in this area. This report summarizes the deliberations of the group and promotes its current guidelines for the integration of this new technique into contemporary clinical practice.

John Chalmers DaCosta (1863-1933): restoration of the old operating table.

John Chalmers DaCosta was an influential chairman and the first Samuel D. Gross Professor of Surgery at Jefferson Medical College in Philadelphia. He was well known throughout the field as a skilled surgeon, passionate speaker, and exceptional writer. In addition to countless accomplishments during his career, DaCosta was deeply dedicated to the preservation and commemoration of surgical history. This ideology was exemplified when he set out on a mission to recover the old wooden operating table used by many of his iconic mentors including Samuel D. Gross, Joseph Pancoast, and William W. Keen. This table was originally used for surgical demonstrations and anatomy lessons in a lecture room of the Ely Building and later in the great amphitheater of the Jefferson Sansom Street Hospital. It was found forgotten in the basement of the College Building and was promptly refurbished, donned with dedicatory plaques, and returned to its honored position in the medical college. Dr. DaCosta also contributed a detailed article recalling the history of the table and the notable leaders in surgery who taught and practiced on its surface. The old table currently stands proudly in the entranceway of the Department of Surgery where it will remain as a cherished symbol of the early beginnings of surgical practice and education.

EZH2 and ALDH1 expression in ductal carcinoma in situ: complex association with recurrence and progression to invasive breast cancer.

The diagnosis of ductal carcinoma in situ (DCIS) is an increasingly common event due to widespread use of screening mammography. However, appropriate clinical management of DCIS is a major challenge in the absence of prognostic markers. Tumor-initiating cells may be particularly relevant for disease pathogenesis; therefore, two markers associated with such cells, EZH2 and ALDH1, were evaluated. A cohort of 248 DCIS patients was used to determine the association of EZH2 and ALDH1 with ipsilateral breast event, DCIS recurrence and progression to invasive breast cancer (IBC). In this cohort, high EZH2 expression was associated with the risk of an ipsilateral breast event and DCIS recurrence but not invasive progression. ALDH1 expression was observed in both the tumor and stromal compartment; however, in neither compartment were ALDH1 levels independently associated with evaluated study endpoints. Interestingly, the combination of high EZH2 with high epithelial ALDH1 was associated with disease progression. Therefore, ALDH1 within the DCIS lesion can add to the prognostic significance of EZH2, particularly in the context of risk of development of invasive disease.

Percutaneous needle vs surgical breast biopsy: previous allegations of overuse of surgery are in error.

PURPOSE: A recent paper in the American Journal of Surgery reported that surgery is used for 30% of breast biopsies, an excessive number. The investigators' stated biopsy volume included Current Procedural Terminology(®) code 19125 ("excision of breast lesion identified by preoperative placement of radiological marker, open"). However, this code may often be used when a surgeon's primary intention is not biopsy but rather excision of a lesion. Therefore, the reported results may overstate the percentage of biopsies performed as surgical procedures. The aim of this study was to more accurately assess the use of percutaneous core needle biopsy (PNB) compared with surgical biopsy. METHODS: The nationwide Medicare Part B databases for 2004 to 2009 were used. Trends in use of codes 19100 (PNB without imaging), 19102 and 19103 (PNB with imaging), 19101 (open biopsy), and the aforementioned 19125 were determined. RESULTS: From 2004 to 2009, the volumes of PNB with imaging (codes 19102 and 19103) increased substantially, while the volume of code 19125 decreased substantially. If one includes all 19125 claims as biopsies, the 2009 frequency of surgical biopsies was 18%. If one considers all 19125 claims as excisions, the frequency of surgical biopsies was 2%. CONCLUSIONS: The previously published statement in the American Journal of Surgery that 30% of breast biopsies are done surgically is erroneous. Medicare data indicate that the true surgical breast biopsy figure is somewhere between 2% and 18%. Given that the recommended rate is 10%, it seems that surgeons and radiologists are collaborating well and that surgical breast biopsy is not being overused.

Retinoblastoma and phosphate and tensin homolog tumor suppressors: impact on ductal carcinoma in situ progression.

BACKGROUND: A subset of patients with ductal carcinoma in situ (DCIS) will progress to invasive breast cancer. However, there are currently no markers to differentiate women at high risk from those at lower risk of developing invasive disease. METHODS: The association of two major tumor suppressor genes, retinoblastoma (RB) and phosphatase and tensin homolog (PTEN), with risk of any ipsilateral breast event (IBE) or progression to invasive breast cancer (IBC) was analyzed using data from 236 DCIS patients treated with breast conserving surgery with long-term follow-up. RB and PTEN expression was assessed with immunohistochemistry. The functional effects of RB and/or PTEN loss were modeled in MCF10A cells. Hazard ratios (HRs) were estimated with univariate and multivariable Cox regression models. All statistical tests were two-sided. RESULTS: Loss of RB immunoreactivity in DCIS was strongly associated with risk of IBE occurrence (HR = 2.64; 95% confidence interval [CI] = 1.64 to 4.25) and IBC recurrence (HR = 4.66; 95% CI = 2.19 to 9.93). The prognostic power of RB loss remained statistically significant in multivariable analyses. PTEN loss occurred frequently in DCIS but was not associated with recurrence or progression. However, patients with DCIS lesions that were both RB and PTEN deficient were at further increased risk for IBEs (HR = 3.39; 95% CI = 1.92 to 5.99) and IBC recurrence (HR = 6.1, 95% CI = 2.5 to 14.76). Preclinical modeling in MCF10A cells demonstrated that loss of RB and PTEN impacted proliferation, motility, and invasive properties. CONCLUSIONS: These studies indicate that RB and PTEN together have prognostic utility and could be used to target aggressive treatment for patients with the greatest probability of benefit.

Axillary sentinel lymph node biopsy after neoadjuvant chemotherapy for carcinoma of the breast.

BACKGROUND: The timing and accuracy of axillary sentinel lymph node biopsy (SLNB) in patients who are receiving neoadjuvant chemotherapy (NACT) for breast cancer are controversial. To examine the accuracy of SLNB after NACT, the authors performed SLNB after chemotherapy on all of patients who received NACT at their institution starting in January 1997. METHODS: Seventy-nine women who underwent NACT between 1997 and 2008 comprised this study and were divided as follows: 4 women had stage I disease, 60 women had stage II disease, and 15 women had stage III disease, including 10 women who had multicentric disease. Thirty-nine women (49.4%) had clinical evidence of axillary metastasis (N1-N2) at the time of diagnosis. The regimen, the duration of treatment, and the number of cycles of NACT depended on clinical response. The choice of breast conservation therapy or mastectomy was based on the patient's response to treatment and patient preference. All patients underwent SLNB after NACT. RESULTS: Seventy-three patients underwent breast conservation therapy, and 6 patients underwent mastectomy. Sentinel lymph nodes were identified in 98.7% of patients (in 1 patient, SLNB failed to capture 1 proven axillary metastasis), and 29 patients underwent full axillary lymph node dissection. Fourteen patients (17.7%) had no residual carcinoma (invasive or ductal carcinoma in situ) in their breast, 5 patients (6.3%) had residual ductal carcinoma in situ (only), and 60 patients (75.9%) had residual invasive carcinoma. One false-negative SLNB was reported in the group of 23 patients who underwent full axillary dissection after a negative SLNB. No patient had a subsequent axillary recurrence. CONCLUSIONS: SLNB after NACT was feasible in virtually all patients and accurately selected patients who required complete level I and II axillary dissection. NACT frequently downstaged the axilla, converting patients with N1-N2 lymph node status to N0 status and also avoiding full axillary dissection in these patients.