Prospective Study of Pain Outcomes Associated With Breast Surgery in Women With Nonhereditary Breast Cancer.

OBJECTIVE: To assess pain severity and interference with life in women after different types of breast cancer surgery and the demographic, treatment-related, and psychosocial variables associated with these pain outcomes. SUMMARY OF BACKGROUND DATA: Data are conflicting regarding pain outcomes and quality of life (QOL) among women who undergo different types of breast surgery. METHODS: Women with nonhereditary breast cancer completed the brief pain inventory before surgery and at 1, 6, 12, and 18 months postsurgery. We assessed associations between pain outcomes and CPM status and mastectomy status using multivariable repeated measures models. We assessed associations between pain outcome and QOL and decision satisfaction. RESULTS: Of 288 women (mean age 56 years, 58% non-Hispanic White), 50 had CPM, 75 had unilateral mastectomy, and 163 had BCS. Mean pain severity scores were higher at one (2.78 vs 1.9, P = 0.016) and 6 months (2.79 vs 1.96, P = 0.031) postsurgery in women who had CPM versus those who did not, but there was no difference at 12 and 18 months. Comparing mastectomy versus BCS, pain severity was higher at 1 and 12 months. There was a significant interaction between pain severity and time point for CPM ( P = 0.006), but not mastectomy status ( P = 0.069). Regardless of surgery type, Black women had higher pain severity ( P = 0.004) than White women. Higher pain interference was associated with lower QOL ( P < 0.001) and lower decision satisfaction ( P = 0.034). CONCLUSIONS: Providers should counsel women considering mastectomy about the potential for greater acute pain and its impact on overall well-being. Racial/ethnic disparities in pain exist and influence pain management in breast surgical patients.

Feasibility of fine-needle aspiration for assessing responses to chemotherapy in metastatic nodes marked with clips in breast cancer: A prospective registry study.

BACKGROUND: Clips are often placed to mark axillary nodes with biopsy-confirmed metastases in patients with breast cancer. The evaluation of clipped nodes after chemotherapy can identify patients who have eradication of nodal disease. The goal of this study was to determine whether preoperative fine-needle aspiration (FNA) of clipped nodes after neoadjuvant chemotherapy (NAC) could predict the presence of residual disease. METHODS: This prospective registry study enrolled 50 patients with a clip placed to mark nodes with biopsy-confirmed metastases who had completed NAC. Participants underwent FNA of the clipped node before seed-localized lymph node excision. FNA pathology was compared with surgical pathology. RESULTS: There were 36 patients (72%) with residual disease on surgical pathology: 3 (8%) had a nondiagnostic aspirate, carcinoma was seen in 14 (39%), and 19 (53%) had a false-negative result. The sensitivity of FNA was 42.4%, its specificity was 100%, and its negative predictive value was 40.6%. In a univariate analysis, the odds of a true-positive result increased significantly with the mean initial size of the clipped node (odds ratio [OR], 4.3; P = .004) and the size of the metastatic focus after NAC (OR, 1.3; P = 0.003), whereas normalization of nodes after chemotherapy (OR, 0.1) and a lack of response on ultrasound (OR, 0.11) were associated with a false-negative result (P = .01). CONCLUSIONS: FNA of marked nodes after chemotherapy has a high false-negative rate. This highlights the need for surgical staging of the axilla after NAC to assess the response.

Ductal Carcinoma In Situ and Margins <2 mm: Contemporary Outcomes With Breast Conservation.

OBJECTIVE: To determine the relationship between negative margin width and locoregional recurrence (LRR) in a contemporary cohort of ductal carcinoma in situ (DCIS) patients. BACKGROUND: Recent national consensus guidelines recommend an optimal margin width of 2 mm or greater for the management of DCIS; however, controversy regarding re-excision remains when managing negative margins <2 mm. METHODS: One thousand four hundred ninety-one patients with DCIS who underwent breast-conserving surgery from 1996 to 2010 were identified from a prospectively managed cancer center database and analyzed using univariate and multivariate Cox proportional hazard models to determine the relationship between negative margin width and LRR with or without adjuvant radiation therapy (RT). RESULTS: A univariate analysis revealed that age <40 years (n = 89; P = 0.02), no RT (n = 298; P = 0.01), and negative margin width <2 mm (n = 120; P = 0.005) were associated with LRR. The association between margin width and LRR differed by adjuvant RT status (interaction P = 0.02). There was no statistical significant difference in LRR between patients with <2 mm and ≥2 mm negative margins who underwent RT (10-yr LRR rate, 4.8% vs 3.3%, respectively; hazard ratio, 0.8; 95% CI, 0.2-3.2; P = 0.72). For patients who did not undergo RT, those with margins <2 mm were significantly more likely to develop a LRR than were those with margins ≥2 mm (10-yr LRR rate, 30.9% vs 5.4%, respectively; hazard ratio, 5.5; 95% CI, 1.8-16.8, P = 0.003). CONCLUSIONS: Routine additional surgery may not be justified for patients with negative margins <2 mm who undergo RT but should be performed in patients who forego RT.

Digital Breast Tomosynthesis for Intraoperative Margin Assessment during Breast-Conserving Surgery.

BACKGROUND: Intraoperative margin assessment for breast cancer patients undergoing segmental mastectomy (SM) enables identification of positive margins, with immediate excision of additional tissue to obtain negative margins. OBJECTIVE: The aim of this study was to determine the ability of digital breast tomosynthesis (DBT) to detect positive margins compared with an institution's standard extensive processing (SEP). METHODS: SM specimens underwent intraoperative SEP with two-dimensional (2D) imaging of the intact and sliced specimen, with review by a breast radiologist and gross assessment by a breast pathologist. Findings guided the surgeon to excise additional tissue. DBT images of intact specimens were prospectively obtained and retrospectively reviewed by a breast radiologist. A positive margin was defined as tumor at ink. RESULTS: Ninety-eight patients underwent 99 SMs. With SEP, 14 (14%) SM specimens had 19 positive margins. SEP did not detect 3 of the 19 positive margins, for a sensitivity of 84%, specificity of 78%, positive predictive value (PPV) of 11%, and negative predictive value (NPV) of 99%. Moreover, DBT did not detect 5 of the 19 positive margins, for a sensitivity of 74% (p > 0.05), specificity of 91% (p < 0.05), PPV of 21.5%, and NPV of 99%. With SEP guidance to excise additional tissue, six cases had final positive margins, with SEP not identifying three of these cases and DBT not identifying two. Pathology from the second surgery of these patients showed either no additional malignancy or only focal ductal carcinoma in situ. CONCLUSIONS: DBT is an accurate method for detecting positive margins in breast cancer patients undergoing SM, performing similar to institutional labor-intensive, intraoperative standard processing.

The role of three-dimensional printing in the surgical management of breast cancer.

A patient-specific 3-dimensional printed model (3DPM) of a woman with breast cancer was created. Mastectomy was favored as BCS would necessitate significant breast size alteration due to the extent of disease. After review of the 3D printed model, the patient and surgeon agreed on breast-conserving surgery. Use of patient-specific 3DPM in the setting of breast cancer may aid patient decision making and surgical planning, leading to enhanced surgical and oncological outcomes.

A Clinical Feasibility Trial for Identification of Exceptional Responders in Whom Breast Cancer Surgery Can Be Eliminated Following Neoadjuvant Systemic Therapy.

OBJECTIVE: To determine the accuracy of fine-needle aspiration (FNA) and vacuum-assisted core biopsy (VACB) in assessing the presence of residual cancer in the breast after neoadjuvant systemic therapy (NST). SUMMARY BACKGROUND DATA: Pathologic complete response (pCR) rates after NST have improved dramatically, suggesting that surgery might be avoided in some patients. Safe avoidance of surgery would require accurate confirmation of no residual invasive/in situ carcinoma. METHODS: Forty patients with T1-3N0-3 triple-negative or HER2-positive cancer receiving NST were enrolled in this single-center prospective trial. Patients underwent ultrasound-guided or mammography-guided FNA and VACB of the initial breast tumor region before surgery. Findings were compared with findings on pathologic evaluation of surgical specimens to determine the performance of biopsy in predicting residual breast disease after NST. RESULTS: Median initial clinical tumor size was 3.3 cm (range, 1.2-7.0 cm); 16 patients (40%) had biopsy-proven nodal metastases. After NST, median clinical tumor size was 1.1 cm (range, 0-4.2 cm). Nineteen patients (47.5%) had a breast pCR and were concordant with pathologic nodal status in 97.5%. Combined FNA/VACB demonstrated an accuracy of 98% (95% CI, 87%-100%), false-negative rate of 5% (95% CI, 0%-24%), and negative predictive value of 95% (95% CI, 75%-100%) in predicting residual breast cancer. VACB alone was more accurate than FNA alone (P = 0.011). CONCLUSIONS: After NST, image-guided FNA/VACB can accurately identify patients with a breast pCR. Based on these results, a prospective clinical trial has commenced in which breast surgery is omitted in patients with a breast pCR after NST according to image-guided biopsy.

Outcomes of Sentinel Lymph Node-Positive Breast Cancer Patients Treated with Mastectomy Without Axillary Therapy.

PURPOSE: Early-stage breast cancer patients with minimal axillary disease identified by sentinel lymph node dissection (SLND) have low regional recurrence rates when treated with breast-conserving surgery and radiation therapy (XRT) and many avoid a completion axillary lymph node dissection (CLND). As the incidence of total mastectomy (TM) has increased, it has become important to characterize which TM patients with a positive SLN may not benefit from further axillary treatment. METHODS: An institutional database was utilized to identify patients treated with a TM for invasive breast cancer and who had a positive SLN from 1994 to 2010. Clinicopathologic factors were analyzed. Regional recurrence rate, recurrence-free survival (RFS), and overall survival (OS) were determined. RESULTS: A total of 525 patients with invasive breast cancer and a positive SLN were treated with TM, including 58 patients who did not have CLND or XRT and 12 patients who did not have CLND but did receive XRT. Median follow-up was 66 months. The incidence of regional recurrence was not significantly different for patients who received no further axillary treatment compared to those who underwent CLND without XRT or those treated with XRT without CLND (10 years rate: 3.8 vs. 1.6 and 0 % respectively). RFS and OS were not significantly different among patients who received no further axillary treatment compared to those who underwent CLND, XRT, or both. CONCLUSIONS: In select patients with early-stage breast cancer treated with mastectomy with a positive SLN, CLND may be avoided without adversely affecting recurrence or survival.

Prospective Study of Surgical Decision-making Processes for Contralateral Prophylactic Mastectomy in Women With Breast Cancer.

OBJECTIVE: We prospectively examined the psychosocial predictors and the decision-making process regarding contralateral prophylactic mastectomy (CPM) among women with sporadic breast cancer. BACKGROUND: Increasing numbers of women with breast cancer are seeking CPM. Data are limited about the surgical decision-making process and the psychosocial factors that influence interest in CPM. METHODS: Women with early-stage unilateral breast cancer (n = 117) were recruited before their first surgical visit at MD Anderson and completed questionnaires assessing knowledge of and interest in CPM and associated psychosocial factors. After the appointment, women and their surgeons completed questions about the extent that various surgical options (including CPM) were discussed; also, the women rated their perceived likelihood of having CPM and the surgeons rated the appropriateness of CPM. RESULTS: Before their first visit, 50% of women were moderately to extremely interested in CPM and 12 (10%) of women had CPM at the time of their primary breast cancer surgery. Less knowledge about breast cancer (P = 0.02) and greater cancer worry (P = 0.03) predicted interest in CPM. Greater cancer worry predicted who had CPM (P = 0.02). Interest in CPM before surgical visit and the likelihood of having CPM after the visit differed (P ≤ 0.001). Surgeons' rating of the appropriateness of CPM and the patient's reported likelihood of having CPM were not significantly different (P = 0.49). CONCLUSIONS: Interest in CPM is common among women with sporadic breast cancer. The informational and emotional aspects of CPM may affect the decision to have CPM and should be addressed when discussing surgical options.

Imaging Factors That Influence Surgical Margins After Preoperative 125I Radioactive Seed Localization of Breast Lesions: Comparison With Wire Localization.

OBJECTIVE: The objective of this study was to compare the potential influence of imaging variables on surgical margins after preoperative radioactive seed localization (RSL) and wire localization (WL) techniques. MATERIALS AND METHODS: A total of 565 women with 660 breast lesions underwent RSL or WL between May 16, 2012, and May 30, 2013. Patient age, lesion type (mass, calcifications, mass with associated calcifications, other), lesion size, number of seeds or wires used, surgical margin status (close positive or negative margins), and reexcision and mastectomy rates were recorded. RESULTS: Of 660 lesions, 127 (19%) underwent RSL and 533 (81%) underwent WL preoperatively. Mean lesion size was 1.8 cm in the RSL group and 1.8 cm in the WL group (p = 0.35). No difference in lesion type was identified in the RSL and WL groups (p = 0.63). RSL with a single seed was used in 105 of 127 (83%) RSLs compared with WL with a single wire in 349 of 533 (65%) WLs (p = 0.0003). The number of cases with a close positive margin was similar for RSLs (26/127, 20%) and WLs (104/533, 20%) (p = 0.81). There was no difference between the RSL group and the WL group in close positive margin status (20% each, p = 0.81), reexcision rates (20% vs 16%, respectively; p = 0.36), or mastectomy rates (6% each, p = 0.96). Lesions containing calcifications were more likely to require more than one wire (odds ratio [OR], 4.44; 95% CI, 2.8-7.0) or more than one seed (OR, 7.03; 95% CI, 1.6-30.0) when compared with masses alone (p < 0.0001). Increasing lesion size and the presence of calcifications were significant predictors of positive margins, whereas the use of more than one wire or seed was not (OR, 0.9; 95% CI, 0.5-1.5) (p = 0.75). CONCLUSION: Close positive margin, reexcision, and mastectomy rates remained similar in the WL group and RSL group. The presence of calcifications and increasing lesion size increased the odds of a close positive margin in both the WL and RSL groups, whereas the use of one versus more than one seed or wire did not.

Breast conservation in the setting of contemporary multimodality treatment provides excellent outcomes for patients with occult primary breast cancer.

PURPOSE: To evaluate recurrence and survival for patients with occult (T0N+) breast cancer who underwent contemporary treatment, assessing outcomes for breast conservation and mastectomy. METHODS: We performed a single-institution review of women with occult breast cancer presenting with axillary metastasis without identifiable breast tumor or distant metastasis. We excluded patients with tumors in the axillary tail or mastectomy specimen, patients with additional nonbreast cancer diagnoses, and patients with a history of breast cancer. Breast conservation was defined as axillary node dissection with radiation therapy, without breast surgery. We evaluated patient, tumor, treatment, and outcome variables. Patients were assessed for local, regional, and distant recurrences. Overall survival was calculated using the Kaplan-Meier method. RESULTS: Thirty-six patients met criteria for occult breast cancer. Most of these patients (77.8 %) had N1 disease. Fifty percent of cancers (n = 18) were estrogen receptor-positive; 12 (33.3 %) were triple-negative. All patients were evaluated with mammography. Thirty-five patients had breast ultrasound (97.2 %) and 33 (91.7 %) had an MRI. Thirty-four patients (94.4 %) were treated with chemotherapy and 33 (91.7 %) with radiotherapy. Twenty-seven patients (75.0 %) were treated with breast conservation. The median follow-up was 64 months. There were no local or regional failures. One distant recurrence occurred >5 years after diagnosis, resulting in a 5-years overall survival rate of 100 %. There were no significant survival differences between patients receiving breast conservation versus mastectomy (p = 0.7). CONCLUSIONS: Breast conservation-performed with contemporary imaging and multimodality treatment-provides excellent local control and survival for women with T0N+ breast cancer and can be safely offered instead of mastectomy.

Incidence and consequence of close margins in patients with ductal carcinoma-in situ treated with mastectomy: is further therapy warranted?

BACKGROUND: The impact of close margins in patients with ductal carcinoma-in situ (DCIS) treated with mastectomy is unclear; however, this finding may lead to a recommendation for postmastectomy radiotherapy (PMRT). We sought to determine the incidence and consequences of close margins in patients with DCIS treated with mastectomy. METHODS: The records of 810 patients with DCIS treated with mastectomy from 1996 through 2009 were reviewed. Clinical and pathologic factors were analyzed with respect to final margin status. Median follow-up was 6.3 years. RESULTS: Overall, 94 patients (11.7 %) had close margins (positive, n = 5; negative but ≤1 mm, n = 54; 1.1-2.9 mm, n = 35). Independent risk factors for close margins included multicentricity, pathologic lesion size ≥1.5 cm, and necrosis, but not age, use of skin-sparing mastectomy, or immediate reconstruction (p > 0.05). Seven patients received PMRT, and none had a locoregional recurrence (LRR). Among the remaining 803 patients, the 10-year LRR rate was 1 % (5.0 % for margins ≤1 mm, 3.6 % for margins 1.1-2.9 mm, and 0.7 % for margins ≥3 mm [p < 0.001]). The 10-year rate of contralateral breast cancer was 6.4 %. On multivariate analysis, close margins was the only independent predictor of LRR (p = 0.005). CONCLUSIONS: Close margins occur in a minority of patients undergoing mastectomy for DCIS and is the only independent risk factor for LRR. As the LRR rate in patients with close margins is low and less than the rate of contralateral breast cancer, PMRT is not warranted except for patients with multiple close/positive margins that cannot be surgically excised.

Prospective Comparison of Toxicity and Cosmetic Outcome After Accelerated Partial Breast Irradiation With Conformal External Beam Radiotherapy or Single-Entry Multilumen Intracavitary Brachytherapy.

PURPOSE: This study aimed to prospectively characterize toxicity and cosmesis after accelerated partial breast irradiation (APBI) with 3-dimensional conformal radiation therapy (CRT) or single-entry, multilumen, intracavitary brachytherapy. METHODS AND MATERIALS: A total of 281 patients with pTis, pT1N0, or pT2N0 (≤3.0 cm) breast cancer treated with segmental mastectomy were prospectively enrolled from December 2008 through August 2014. APBI was delivered using 3-dimensional CRT (n = 29) or with SAVI (n = 176), Contura (n = 56), or MammoSite (n = 20) brachytherapy catheters. Patients were evaluated at protocol-specified intervals, at which time the radiation oncologist scored cosmetic outcome, toxicities, and recurrence status using a standardized template. RESULTS: The median follow-up time is 41 months. Grade 1 seroma and fibrosis were more common with brachytherapy than with 3-dimensional CRT (50.4% vs 3.4% for seroma; P < .0001 and 66.3% vs 44.8% for fibrosis; P = .02), but grade 1 edema was more common with 3-dimensional CRT than with brachytherapy (17.2% vs 5.6%; P = .04). Grade 2 to 3 pain was more common with 3-dimensional CRT (17.2% vs 5.2%; P = .03). Actuarial 5-year rates of fair or poor radiation oncologist-reported cosmetic outcome were 9% for 3-dimensional CRT and 24% for brachytherapy (P = .13). Brachytherapy was significantly associated with inferior cosmesis on mixed model analysis (P = .003). Significant predictors of reduced risk of adverse cosmetic outcome after brachytherapy were D0.1cc (skin) ≤102%, minimum skin distance >5.1 mm, dose homogeneity index >0.54, and volume of nonconformance ≤0.89 cc. The 5-year ipsilateral breast recurrence was 4.3% for brachytherapy and 4.2% for 3-dimensional CRT APBI patients (P = .95). CONCLUSIONS: Brachytherapy APBI is associated with higher rates of grade 1 fibrosis and seroma than 3-dimensional CRT but lower rates of grade 1 edema and grade 2 to 3 pain than 3-dimensional CRT. Rates of radiation oncologist-reported fair or poor cosmetic outcomes are higher with brachytherapy. We identified dosimetric parameters that predict reduced risk of adverse cosmetic outcome after brachytherapy-based APBI. Ipsilateral breast recurrence was equivalent for brachytherapy and 3-dimensional CRT.

Sentinel node biopsy is important in mastectomy for ductal carcinoma in situ.

BACKGROUND: There is uncertainty about the utility of sentinel node biopsy (SNB) for ductal carcinoma in situ (DCIS) and its potential to avoid axillary lymph node dissection (ALND) in patients undergoing mastectomy for DCIS. METHODS: A review was conducted of 179 patients who underwent mastectomy with sentinel node biopsy for DCIS without invasion or microinvasion on premastectomy pathology review. RESULTS: The sentinel node identification rate was 98.9% (177/179). Twenty (11.3%) of 177 mastectomies for DCIS had a positive SNB: two micrometastasis (pN1mi) and 18 isolated tumor cells [pN0(i+)]. Unsuspected invasive cancer was found in 20 (11.2%) of 179 mastectomies, eight T1mic, five T1a, three T1b, and four T1c tumors. Sentinel nodes were identified in 19 of 20 patients with invasive cancer and four were positive: one pN1mi and three pN0(i+). Eighteen of 19 patients with unsuspected invasive cancer were able to avoid axillary dissection on the basis of SNB results. Of the 159 patients whose final pathology revealed DCIS without invasion, a sentinel node was identified in 158 (99.4%). The SNB was positive in 16 patients (10.1%): one pN1mi and 15 pN0(i+). Three patients underwent ALND on the basis of positive SNBs and in each the SNB was the only positive node. CONCLUSIONS: 11% of patients undergoing mastectomy for DCIS were found to have invasive cancer on final pathology. The use of SNB during mastectomy for DCIS allowed nearly all such patients to avoid axillary dissection. These results support routine use of SNB during mastectomy for DCIS.

Prospective Study of Psychosocial Outcomes of Having Contralateral Prophylactic Mastectomy Among Women With Nonhereditary Breast Cancer.

Purpose The incidence of contralateral prophylactic mastectomy (CPM) has continued to increase. We prospectively examined psychosocial outcomes before and up to 18 months after surgery in women who did or did not have CPM. Methods Women with unilateral, nonhereditary breast cancer completed questionnaires before and 1, 6, 12, and 18 months after surgery. Primary psychosocial measures were cancer worry and cancer-specific distress. Secondary measures were body image, quality of life (QOL), decisional satisfaction, and decisional regret. Results A total of 288 women (mean age, 56 years; 58% non-Hispanic white) provided questionnaire data, of whom 50 underwent CPM. Before surgery, women who subsequently received CPM had higher cancer distress ( P = .04), cancer worry ( P < .001), and body image concerns ( P < .001) than women who did not have CPM. In a multivariable repeated measures model adjusted for time, age, race/ethnicity, and stage, CPM was associated with more body image distress ( P < .001) and poorer QOL ( P = .02). There was a significant interaction between time point and CPM group for cancer worry ( Pinteraction < .001), suggesting that CPM patients had higher presurgery cancer worry, but their postsurgery worry decreased over time and was similar to the worry of patients who did not have CPM. QOL was similar between CPM groups before surgery but declined 1 month after surgery and remained lower than patients who did not have CPM after surgery ( Pinteraction = .05). Conclusion These results may facilitate informed discussions between women and their physicians regarding CPM. Fear and worry may be foremost concerns at the time surgical decisions are made, when women may not anticipate the adverse future effect of CPM on body image and QOL.

Identification of Patients With Documented Pathologic Complete Response in the Breast After Neoadjuvant Chemotherapy for Omission of Axillary Surgery.

Importance: A pathologic complete response (pCR; no invasive or in situ cancer) occurs in 40% to 50% of patients with HER2-positive (HER2+) and triple-negative (TN) breast cancer. The need for surgery if percutaneous biopsy of the breast after neoadjuvant chemotherapy (NCT) indicates pCR in the breast (hereinafter referred to as breast pCR) has been questioned, and appropriate management of the axilla in such patients is unknown. Objective: To identify patients among exceptional responders to NCT with a low risk for axillary metastases when breast pCR is documented who may be eligible for an omission of surgery clinical trial design. Design, Setting, and Participants: This prospective cohort study at a single-institution academic national comprehensive cancer center included 527 consecutive patients with HER2+/TN (T1/T2 and N0/N1) cancer treated with NCT followed by standard breast and nodal surgery from January 1, 2010, through December 31, 2014. Main Outcomes and Measures: Patients who achieved a breast pCR were compared with patients who did not based on subtype, initial ultrasonographic findings, and documented pathologic nodal status. Incidence of positive findings for nodal disease on final pathologic review was calculated for patients with and without pCR and compared using relative risk ratios with 95% CIs. Results: The analysis included 527 patients (median age, 51 [range, 23-84] years). Among 290 patients with initial nodal ultrasonography showing N0 disease, 116 (40.4%) had a breast pCR and 100% had no evidence of axillary lymph node metastases after NCT. Among 237 patients with initial biopsy-proved N1 disease, 69 of 77 (89.6%) with and 68 of 160 (42.5%) without a breast pCR had no evidence of residual nodal disease (P < .01). Patients without a breast pCR had a relative risk for positive nodal metastases of 7.4 (95% CI, 3.7-14.8; P < .001) compared with those with a breast pCR. Conclusions and Relevance: Breast pCR is highly correlated with nodal status after NCT, and the risk for missing nodal metastases without axillary surgery in this cohort is extremely low. These data provide the fundamental basis and rationale for management of the axilla in clinical trials of omission of cancer surgery when image-guided biopsy indicates a breast pCR.

A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors.

Background: Breast cancer patients who do not respond to neoadjuvant therapy have a poor prognosis. There is a pressing need for novel targets and models for preclinical testing. Here we report characterization of breast cancer patient-derived xenografts (PDX) largely generated from residual tumors following neoadjuvant chemotherapy.Experimental Design: PDXs were derived from surgical samples of primary or locally recurrent tumors. Normal and tumor DNA sequencing, RNASeq, and reverse phase protein arrays (RPPA) were performed. Phenotypic profiling was performed by determining efficacy of a panel of standard and investigational agents.Results: Twenty-six PDXs were developed from 25 patients. Twenty-two were generated from residual disease following neoadjuvant chemotherapy, and 24 were from triple-negative breast cancer (TNBC). These PDXs harbored a heterogeneous set of genomic alterations and represented all TNBC molecular subtypes. On RPPA, PDXs varied in extent of PI3K and MAPK activation. PDXs also varied in their sensitivity to chemotherapeutic agents. PI3K, mTOR, and MEK inhibitors repressed growth but did not cause tumor regression. The PARP inhibitor talazoparib caused dramatic regression in five of 12 PDXs. Notably, four of five talazoparib-sensitive models did not harbor germline BRCA1/2 mutations, but several had somatic alterations in homologous repair pathways, including ATM deletion and BRCA2 alterations.Conclusions: PDXs capture the molecular and phenotypic heterogeneity of TNBC. Here we show that PARP inhibition can have activity beyond germline BRCA1/2 altered tumors, causing regression in a variety of molecular subtypes. These models represent an opportunity for the discovery of rational combinations with targeted therapies and predictive biomarkers. Clin Cancer Res; 23(21); 6468-77. ©2017 AACR.

Transection of Radioactive Seeds in Breast Specimens.

Radioactive seed localization is a new procedure for localizing breast lesions that has several advantages over the standard wire-localization procedure. It is reported to be safe for both patients and medical personnel. Although it is theoretically possible to transect the titanium-encapsulated seed while processing the breast specimen in the pathology laboratory, the likelihood of such an event is thought to be exceedingly low. In fact, there are no previous reports of such an event in the literature to date. We recently encountered 2 cases in which a radioactive seed was inadvertently transected while slicing a breast specimen at the grossing bench. In this report, we describe each case and offer recommendations for minimizing radioactive exposure to personnel and for preventing radioactive contamination of laboratory equipment.

Improved Axillary Evaluation Following Neoadjuvant Therapy for Patients With Node-Positive Breast Cancer Using Selective Evaluation of Clipped Nodes: Implementation of Targeted Axillary Dissection.

PURPOSE: Placing clips in nodes with biopsy-confirmed metastasis before initiating neoadjuvant therapy allows for evaluation of response in breast cancer. Our goal was to determine if pathologic changes in clipped nodes reflect the status of the nodal basin and if targeted axillary dissection (TAD), which includes sentinel lymph node dissection (SLND) and selective localization and removal of clipped nodes, improves the false-negative rate (FNR) compared with SLND alone. METHODS: A prospective study of patients with biopsy-confirmed nodal metastases with a clip placed in the sampled node was performed. After neoadjuvant therapy, patients underwent axillary surgery and the pathology of the clipped node was compared with other nodes. Patients undergoing TAD had SLND and selective removal of the clipped node using iodine-125 seed localization. The FNR was determined in patients undergoing complete axillary lymphadenectomy (ALND). RESULTS: Of 208 patients enrolled in this study, 191 underwent ALND, with residual disease identified in 120 (63%). The clipped node revealed metastases in 115 patients, resulting in an FNR of 4.2% (95% CI, 1.4 to 9.5) for the clipped node. In patients undergoing SLND and ALND (n = 118), the FNR was 10.1% (95% CI, 4.2 to 19.8), which included seven false-negative events in 69 patients with residual disease. Adding evaluation of the clipped node reduced the FNR to 1.4% (95% CI, 0.03 to 7.3; P = .03). The clipped node was not retrieved as an SLN in 23% (31 of 134) of patients, including six with negative SLNs but metastasis in the clipped node. TAD followed by ALND was performed in 85 patients, with an FNR of 2.0% (1 of 50; 95% CI, 0.05 to 10.7). CONCLUSION: Marking nodes with biopsy-confirmed metastatic disease allows for selective removal and improves pathologic evaluation for residual nodal disease after chemotherapy.

Ability to Generate Patient-Derived Breast Cancer Xenografts Is Enhanced in Chemoresistant Disease and Predicts Poor Patient Outcomes.

BACKGROUND: Breast cancer patients who are resistant to neoadjuvant chemotherapy (NeoCT) have a poor prognosis. There is a pressing need to develop in vivo models of chemo resistant tumors to test novel therapeutics. We hypothesized that patient-derived breast cancer xenografts (BCXs) from chemo- naïve and chemotherapy-exposed tumors can provide high fidelity in vivo models for chemoresistant breast cancers. METHODS: Patient tumors and BCXs were characterized with short tandem repeat DNA fingerprinting, reverse phase protein arrays, molecular inversion probe arrays, and next generation sequencing. RESULTS: Forty-eight breast cancers (24 post-chemotherapy, 24 chemo-naïve) were implanted and 13 BCXs were established (27%). BCX engraftment was higher in TNBC compared to hormone-receptor positive cancer (53.8% vs. 15.6%, p = 0.02), in tumors from patients who received NeoCT (41.7% vs. 8.3%, p = 0.02), and in patients who had progressive disease on NeoCT (85.7% vs. 29.4%, p = 0.02). Twelve patients developed metastases after surgery; in five, BCXs developed before distant relapse. Patients whose tumors developed BCXs had a lower recurrence-free survival (p = 0.015) and overall survival (p<0.001). Genomic losses and gains could be detected in the BCX, and three models demonstrated a transformation to induce mouse tumors. However, overall, somatic mutation profiles including potential drivers were maintained upon implantation and serial passaging. One BCX model was cultured in vitro and re-implanted, maintaining its genomic profile. CONCLUSIONS: BCXs can be established from clinically aggressive breast cancers, especially in TNBC patients with poor response to NeoCT. Future studies will determine the potential of in vivo models for identification of genotype-phenotype correlations and individualization of treatment.

A scientist revisits the atrophy-hypertrophy complex: hepatic apoptosis and regeneration.

In 1898, Cantlie demonstrated his deep insight into the AHC when he wrote. "It is theoretically possible to tie the vessels of one side at the gate of the liver...leaving the other side to do the work. That one-half of the liver can hypertrophy, so as to perform the function of the whole, is attested by pathological study...I commend this subject to all those who are working on the surgery of the liver; and I believe that if, in the hands of future observers, the statements I have made receive closer investigation, surgery of the liver will be advanced a step." More than 100 years later, his foresight is coming to fruition, but the understanding of the AHC remains rudimentary. Further insight into the cellular and molecular mechanisms that initiate hepatocyte replication after contralateral atrophy may allow the development of novel therapeutic treatments or adjuncts.