Efficacy of Neoadjuvant Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohorts.

PURPOSE: Recent studies demonstrate that addition of neoadjuvant (NA) carboplatin to anthracycline/taxane chemotherapy improves pathologic complete response (pCR) in triple-negative breast cancer (TNBC). Effectiveness of anthracycline-free platinum combinations in TNBC is not well known. Here, we report efficacy of NA carboplatin + docetaxel (CbD) in TNBC. EXPERIMENTAL DESIGN: The study population includes 190 patients with stage I-III TNBC treated uniformly on two independent prospective cohorts. All patients were prescribed NA chemotherapy regimen of carboplatin (AUC 6) + docetaxel (75 mg/m2) given every 21 days × 6 cycles. pCR (no evidence of invasive tumor in the breast and axilla) and residual cancer burden (RCB) were evaluated. RESULTS: Among 190 patients, median tumor size was 35 mm, 52% were lymph node positive, and 16% had germline BRCA1/2 mutation. The overall pCR and RCB 0 + 1 rates were 55% and 68%, respectively. pCRs in patients with BRCA-associated and wild-type TNBC were 59% and 56%, respectively (P = 0.83). On multivariable analysis, stage III disease was the only factor associated with a lower likelihood of achieving a pCR. Twenty-one percent and 7% of patients, respectively, experienced at least one grade 3 or 4 adverse event. CONCLUSIONS: The CbD regimen was well tolerated and yielded high pCR rates in both BRCA-associated and wild-type TNBC. These results are comparable with pCR achieved with the addition of carboplatin to anthracycline-taxane chemotherapy. Our study adds to the existing data on the efficacy of platinum agents in TNBC and supports further exploration of the CbD regimen in randomized studies. Clin Cancer Res; 23(3); 649-57. ©2016 AACR.

Impact of neoadjuvant chemotherapy on axillary nodal involvement in patients with clinically node negative triple negative breast cancer.

BACKGROUND: We evaluated the impact of Neoadjuvant Chemotherapy (NAC) versus primary surgery (PS) on axillary disease burden/surgery in clinically node negative Triple Negative Breast Cancer (TNBC). METHODS: Two hundred forty-three Stage I-III TNBC patients have enrolled on an IRB approved multisite prospective registry. Clinical and treatment information was collected. RESULTS: One hundred fifty-five patients with clinically node negative TNBC were identified. 47%, 49%, and 4% of patients had T1, T2, and T3 disease, respectively. Patients underwent PS (103/155, 66%) or NAC (52/155, 34%) at the discretion of treating physicians. 17% of PS and 0% of NAC patients were node positive at surgery (P=0.006). For T2 disease, 32% of PS and 0% of NAC patients were node positive at surgery (P=0.001). NAC patients had a lower chance of positive SLNB (0% vs. 12%, P=0.004) and undergoing ALND (2% vs. 22%, P=0.001) than PS patients. CONCLUSION: In this clinically node negative TNBC cohort, all NAC-treated patients were node negative at surgery, whereas 17% of PS patients had involved axillary nodes. NAC should be considered for clinically node negative TNBC to reduce the extent of axillary surgery even if breast conservation is not planned.

Bilateral diffuse tumorous pseudoangiomatous stromal hyperplasia: a case of bilateral mastectomy in a 29-year-old woman.

Pseudoangiomatous stromal hyperplasia (PASH) is a benign breast lesion commonly encountered as an incidental microscopic finding. However, it can also manifest as a mass-forming lesion (tumorous PASH) capable of recurrence after surgical excision. Most of the previously reported cases of tumorous PASH present as a single dominant mass. Here we reported a rare case of diffuse tumorous PASH involving bilateral breasts clinically mimicking malignancy. A 29-year-old African-American female presented with a one-year history of bilateral breast enlargement and asymmetry. Physical examination revealed multiple palpable nodules in bilateral breasts. Imaging studies demonstrated innumerable homogeneously enhancing masses throughout both breasts, greater on the left, with multiple cysts and edema. Biopsy of the breast nodules demonstrated histopathological changes consistent with PASH. Due to the extent of the lesions and progressive clinical symptoms, decision was made to perform bilateral mastectomy. Macroscopic examination of the bilateral mastectomy specimens revealed markedly enlarged breasts with marked edema and numerous well-defined firm nodules. Microscopic evaluation of the nodules confirmed the diagnosis of PASH. No evidence of malignancy was identified. Recognition of this rare form of PASH is essential for the proper clinical management.

Commentary on the Canadian National Breast Screening study.

In the setting of the 25-year follow-up of the Canadian National Breast Screening Study, the Society of Surgical Oncology continues to endorse mammographic screening for women beginning at 40 years of age, while acknowledging that mammography has both risks and benefits. Further investigation is warranted to develop better screening methods and to determine optimal screening schedules for women based on their risk of future breast cancer and their imaging characteristics.

Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing.

NCCN guidelines recommend genetic testing for all triple-negative breast cancer (TNBC) patients aged ≤60 years. However, due to the lack of prospective information in unselected patients, these guidelines are not uniformly adopted by clinicians and insurance carriers. The aim of this study was to determine the prevalence of BRCA mutations and evaluate the utility of NCCN guidelines in unselected TNBC population. Stage I-IV TNBC patients were enrolled on a prospective registry at academic and community practices. All patients underwent BRCA1/2 testing. Significant family history (SFH) was defined >1 relative with breast cancer at age ≤50 or ≥1 relative with ovarian cancer. Mutation prevalence in the entire cohort and subgroups was calculated. 207 TNBC patients were enrolled between 2011 and 2013. Racial/ethnic distribution: Caucasian (80 %), African-American (14 %), Ashkenazi (1 %). Deleterious BRCA1/2 mutations were identified in 15.4 % (32/207) of patients (BRCA1:11.1 %, BRCA2:4.3 %). SFH reported by 36 % of patients. Mutation prevalence in patients with and without SFH was 31.6 and 6.1 %, respectively. When assessed by age at TNBC diagnosis, the mutation prevalences were 27.6 % (≤50 years), 11.4 % (51-60 years), and 4.9 % (≥61 years). Using SFH or age ≤50 as criteria, 25 and 34 % of mutations, respectively, were missed. Mutation prevalence in patients meeting NCCN guidelines was 18.3 % (32/175) and 0 % (0/32) in patients who did not meet guidelines (p = .0059). In this unselected academic and community population with negligible Ashkenazi representation, we observed an overall BRCA mutation prevalence rate of 15.4 %. BRCA testing based on NCCN guidelines identified all carriers supporting its routine application in clinical practice for TNBC.

Procyanidin induces apoptosis of esophageal adenocarcinoma cells via JNK activation of c-Jun.

Procyanidins are polymeric flavanols found in fruits and vegetables and have shown anticarcinogenic/chemopreventive properties. We previously showed that oligomeric procyanidin extracted from apples induced cell cycle arrest and apoptosis in esophageal adenocarcinoma (OA) cells. To understand the mechanism of action, we determined transcriptomic changes induced by procyanidin in OA cells. Pathway analysis implicated mitogen-activated protein kinase signaling pathways in eliciting these responses. Procyanidin induced the activation of JNK and p38 and the phosphorylation and expression of c-Jun. Inhibition of JNK but not p38 kinase activity prevented the procyanidin-induced phosphorylation and expression of c-Jun. Knockdown of the expression of JNK1, JNK2, or JUN diminished procyanidin-induced effects on cell proliferation and apoptosis. c-Jun is a component of the transcription factor AP-1 and AP-1 binding sites are overrepresented in the promoters of procyanidin-induced genes. This indicates that JNK activation of c-Jun by procyanidin leads to the induction of apoptosis of OA cells and suggests a role for a c-Jun-mediated transcriptional program. These data provide a mechanistic understanding of how procyanidin specifically targets a distinct pathway involved in the induction of apoptosis in OA cells and will inform future studies investigating its use as a chemopreventive/therapeutic agent.

Axillary reverse mapping: a prospective study in women with clinically node negative and node positive breast cancer.

BACKGROUND: The primary aim of axillary reverse mapping (ARM) is to prevent lymphedema by preserving arm versus breast axillary lymphatics. Concerns regarding feasibility and oncologic safety have limited the adoption of the technique. This prospective study was undertaken to investigate ARM in clinically node negative and node positive breast cancer patients. METHODS: A total of 184 patients underwent 212 ARM procedures: 155 sentinel lymph node biopsies (SLNB) without axillary lymph node dissection (ALND) (group 1) and 57 ALNDs with/without SLNB (group 2). ARM lymphatics were not preserved if they were a SLN, directly entered a SLN, or were within ALND boundaries during ALND. RESULTS: SLN with radioisotope alone was successful in 92 % of procedures (181 of 197). ARM identification was 47 % (73 of 155) in group 1. Criteria were met in 30 % (47 of 155) for preservation, and 25 % (38 of 155) were preserved. Of those who met preservation criteria, 81 % (38 of 47) were preserved. In group 2, ARM identification was 72 % (41 of 57); 7 met criteria for preservation and were preserved. Of the ARM nodes, 10 % (22 of 212) were SLNs (crossover). ARM nodes contained metastatic disease in one crossover and two nonsentinel ARM nodes in clinically node positive patients with N2/N3 disease. CONCLUSIONS: ARM is a feasible technique for identification and preservation of axillary arm lymphatics with an acceptable incidence of SLN crossover. A larger sample size is needed to determine if ARM can reduce the incidence of lymphedema in patients undergoing SLNB alone and to confirm the absence of ARM metastases in clinically node negative patients undergoing ALND.

Adjuvant endocrine therapy for the surgeon: options, side effects, and their management.

Adjuvant endocrine therapy is often advised for women with hormone receptor positive breast cancer. In premenopausal women, tamoxifen is the primary endocrine therapy option since aromatase inhibitors (AIs) are contraindicated in patients with residual ovarian function. The benefit of ovarian ablation/suppression in premenopausal patients remains controversial. In postmenopausal ER positive patients, treatment with an AI alone, switching strategies with an AI and tamoxifen, or extended therapy with an AI after 5 years of tamoxifen are superior to 5 years of tamoxifen alone. While the data supporting the use of endocrine therapy for ER positive breast cancer is clear, adverse effects occur with variable frequency and severity. The intensity and severity of the most common endocrine therapy adverse effects are mild to moderate for the majority of women, and serious life-threatening adverse effects are uncommon. However, compliance issues are often larger than recognized. Good communication with patients is critical to address concerns and symptoms, and more research is needed to identify effective methods to minimize treatment side effects.

Outcomes of breast cancer patients with micrometastases and isolated tumor cells in sentinel lymph nodes.

BACKGROUND: The prognostic value and clinical implication of micrometastases and isolated tumor cells (ITCs) in sentinel lymph nodes are still not clearly defined. This study was designed to collect clinical pathological data in our Institution. PATIENTS AND METHODS: Twenty-five cases of micrometastases and nine cases of ITCs were identified among 1,000 sentinel lymph node biopsies performed at our institution in the last 10 years. RESULTS: In the 25 patients with sentinel node micrometastases, 12 had completion axillary node dissection, and only one of these twelve had non-sentinel node micrometastasis. In this group, two patients developed local recurrence, and two patients developed distant metastases (one with and one without prior local recurrence) and later died. Both patients had negative non-sentinel lymph nodes. In the 9 patients with sentinel node ITCs, no patient had completion axillary node dissection and no patient developed local or distant metastases. CONCLUSION: Completion axillary node dissection may not be necessary in patients with sentinel node micrometastases and ITCs as it does not impact local recurrence. ITCs do not seem to have prognostic significance. Micrometastases, however, may be associated with local and/or distant metastasis.

Solitary positive sentinel lymph node accompanied by negative sentinel lymph node(s) is predictive of a negative completion axillary lymph node dissection.

BACKGROUND: Many patients with a positive sentinel lymph node (SLN) have a negative axillary lymph node dissection (ALND). We hypothesized that a solitary positive SLN associated with at least 1 negative SLN is predictive of a negative completion ALND. Omission of ALND may be possible in these patients. METHODS: A retrospective review of 392 consecutive patients who underwent SLNB was performed. The 78 (20%) SLN-positive patients were divided into 4 groups: group 1: solitary positive SLN associated with at least 1 negative SLN; group 2: more than 1 positive SLN with at least 1 negative SLN; group 3: solitary positive SLN with no additional SLNs; and group 4: more than 1 positive SLN and all SLNs positive. RESULTS: Excluding extracapsular extension, only 3% of group 1 patients had a positive ALND. Positive ALND was found in 15% of group 2, 29% of group 3, and 77% of group 4. CONCLUSIONS: A solitary positive SLN accompanied by additional negative SLN(s) is predictive of a negative completion ALND.

Grading invasive ductal carcinoma of the breast: advantages of using automated proliferation index instead of mitotic count.

Breast carcinomas are graded according to the "Nottingham modification of the Bloom-Richardson system" (SBR). The system is hindered, however, by lack of precision in assessing all three parameters including nuclear grade, mitosis, and tubular formation, leading to an element of subjectivity. Our objective was to evaluate a new grading system [the nuclear grade plus proliferation (N+P) system] for subjectivity, ease, and better representation of tumor biology. Its components are nuclear grade and automated proliferation index. Invasive ductal carcinomas, consisting of 137 SBR grade I, 247 grade II, and 266 grade III, were re-evaluated by the N+P system. The two systems were compared with each other and correlated with patients' overall survival, tumor size, angiolymphatic invasion, lymph node status, and biomarker status including estrogen receptor, progesterone receptor, p53, epidermal growth factor receptor, BCL-2, and Her-2. Although there was an agreement between the two systems with histologic and prognostic parameters studied, there was 37% disagreement when grading individual tumors. Fifty-three percent of SBR grade II tumors were "down-graded" to N+P grade I, and 7% were "up-graded" to N+P grade III. Distinction among the different histologic grades for overall survival curves was better indicated by the N+P than the SBR system.

A comparison of prognostic tumor markers obtained on image-guided breast biopsies and final surgical specimens.

BACKGROUND: This study was initiated to determine whether tumor markers obtained on image-guided breast biopsy specimens provide accurate prognostic information for women with invasive breast cancer. METHODS: Prognostic tumor markers on preoperative image-guided biopsy and final surgical specimens were compared in 44 patients with invasive breast cancer. RESULTS: Progesterone receptor (PR) discordance was 18%. In 87% of PR discordant cases, the image-guided biopsy was positive and the final specimen was negative (P = 0.03). Tumor grade was discordant in 36% of patients Discordance for estrogen receptor (ER) = 2%; MIB-1 = 18%; Her2/neu = 9%; EGFR = 10%; p53 = 9%; and bcl-2 = 0%. The discordance for these markers was random and did not reach statistical significance. CONCLUSION: Image-guided core needle biopsies provide reliable information for the majority of prognostic tumor makers. A positive progesterone receptor is significantly more likely to be determined by core biopsy rather than the final surgical specimen. Tumor grade should be based upon the final surgical specimen whenever possible.

Factors associated with success of the extreme drug resistance assay in primary breast cancer specimens.

The extreme drug resistance (EDR) assay has not been widely studied in the setting of non-metastatic breast cancer. We evaluated the feasibility of performing the assay in 144 primary breast tumor specimens from two institutions by determining the rate of successful tumor culture for assays, number of drugs evaluated per assay, and time from tumor biopsy to receipt of results. We also sought to determine factors that are associated with assay success. An exploratory analysis was performed to detect possible associations between estrogen receptor (ER), progesterone receptor (PR) and HER2/NEU over-expression and extreme drug resistance demonstrated by the assay for specific chemotherapeutic agents. Of 144 tumor specimens submitted, tumor was successfully cultured for assay in 101(70%) of cases. A median of five drugs was evaluated per assay (range 2-9). Results were obtained in a median of 8 days (range 2-29). Young age, high tumor grade, PR negativity, and higher tumor submission weight were predictive for a successful assay. EDR was observed in 7-15% of tumors to doxorubicin, cyclophosphamide, 5-fluorouracil (5FU) and mitoxantrone, but EDR to paclitaxel was observed in 35%. Extreme drug resistance to 5-FU was associated with negative ER and PR status. There was a trend toward association between EDR to paclitaxel and HER2/NEU over-expression. The EDR assay may be successfully performed in the majority of tumors, and assay results are available in a timely fashion such that adjuvant treatment drug selection could be guided by results. These results may be helpful for designing possible future trials that evaluate the assay's role in adjuvant chemotherapy selection.