Incidence, characteristics, and management of central nervous system metastases in patients with inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have a high risk of central nervous system metastasis (mCNS). The purpose of this study was to quantify the incidence of and identify risk factors for mCNS in patients with IBC. METHODS: The authors retrospectively reviewed patients diagnosed with IBC between 1997 and 2019. mCNS-free survival time was defined as the date from the diagnosis of IBC to the date of diagnosis of mCNS or the date of death, whichever occurred first. A competing risks hazard model was used to evaluate risk factors for mCNS. RESULTS: A total of 531 patients were identified; 372 patients with stage III and 159 patients with de novo stage IV disease. During the study, there were a total of 124 patients who had mCNS. The 1-, 2-, and 5-year incidence of mCNS was 5%, 9%, and 18% in stage III patients (median follow-up: 5.6 years) and 17%, 30%, and 42% in stage IV patients (1.8 years). Multivariate analysis identified triple-negative tumor subtype as a significant risk factor for mCNS for stage III patients. For patients diagnosed with metastatic disease, visceral metastasis as first metastatic site, triple-negative subtype, and younger age at diagnosis of metastases were risk factors for mCNS. CONCLUSIONS: Patients with IBC, particularly those with triple-negative IBC, visceral metastasis, and those at a younger age at diagnosis of metastatic disease, are at significant risk of developing mCNS. Further investigation into prevention of mCNS and whether early detection of mCNS is associated with improved IBC patient outcomes is warranted.

Long-term outcomes of breast-conserving therapy for women with ductal carcinoma in situ.

PURPOSE: Improved imaging, surgical techniques, and pathologic evaluation likely have decreased local recurrence rates for patients with ductal carcinoma in situ (DCIS). We present long-term outcomes of a large single-institution series after breast-conserving surgery (BCS) and adjuvant radiation therapy (RT). METHODS: We retrospectively reviewed the records of 245 women treated for DCIS with BCS and RT between 2001 and 2007. Competing risk analysis was used to calculate local recurrence (LR) as a first event with the development of a second non-breast malignancy, contralateral breast cancer, and death as competing first events. RESULTS: At a median follow-up of 10.6 years, 4 patients had a LR (2 DCIS, 2 invasive) as a first event with a cumulative LR incidence of 0.0% and 1.5% at 5 and 10 years, respectively. Most patients had > 2 mm margins (90%), specimen radiographs (93%), and received a tumor bed boost (99%). The majority (60%) of patients with hormone receptor-positive disease received adjuvant endocrine therapy. Ten-year cumulative incidence of contralateral breast cancer (CBC) was 7.9%, second non-breast malignancy was 4.5%, and death unrelated to breast cancer was 3.5%. Family history, age at diagnosis, and receipt of endocrine therapy were not significantly associated with the development of CBC (all P > 0.05). CONCLUSIONS: With mature follow-up, our rates of local recurrence following breast-conserving therapy for DCIS remain very low (1.5% at 10 years). The incidence of CBC was higher than the LR incidence. Predisposing factors for the development of CBC are worthy of investigation.

The Current and Evolving Role of Radiation Therapy for Central Nervous System Metastases from Breast Cancer.

PURPOSE OF REVIEW: For patients with breast cancer who develop brain metastases, radiation therapy (RT) provides local control. Here, we review the current role for central nervous system RT, particularly focusing on the evolving role for stereotactic radiosurgery (SRS). RECENT FINDINGS: SRS treats only known CNS disease as opposed to whole-brain radiation therapy (WBRT), which treats the entire brain parenchyma. SRS has been found to cause less neurocognitive decline than WBRT. SRS is currently utilized in patients with four or fewer brain metastases, but several ongoing trials are examining the use of SRS for greater than four metastases. For patients requiring WBRT, hippocampal avoidance WBRT and memantine concurrent with and adjuvant to WBRT have been found to reduce the risk of neurocognitive decline. Both SRS and WBRT are used as a local therapy for brain metastases. SRS is increasingly preferred given fewer long-term neurocognitive side effects.

Body Mass Index and Locoregional Recurrence in Women with Early-Stage Breast Cancer.

BACKGROUND: Higher body mass index (BMI) has been associated with increased distant recurrence and decreased survival for women with breast cancer. However, the relationship between BMI and locoregional recurrence (LRR) has been less well studied and was therefore the subject of this investigation. METHODS: The study identified 878 women with early-stage invasive breast cancer who underwent breast-conservation therapy (BCT) between June 1997 and October 2007. Time from diagnosis to LRR was calculated using a competing risk analysis with contralateral breast cancer (CBC), distant metastases (DM), and death as the competing risks. Gray's competing risks analysis, which included an interaction term between menopausal status and BMI, was used to identify significant risk factors for the development of LRR. RESULTS: After a median follow-up period of 10.8 years, LRR was diagnosed as a first event for 45 women. In a multivariable analysis, BMI was positively associated with LRR but only in premenopausal women. Specifically, when these women were compared with normal- and underweight women, both the overweight women (hazard ratio (HR), 2.97; 95 % confidence interval (CI) 1.04-8.46; p = 0.04) and the obese women (HR, 3.36; 95 % CI 1.07-10.63; p = 0.04) showed a higher risk of LRR. A similar association between BMI and disease-free survival was noted for premenopausal but not postmenopausal women. CONCLUSION: For premenopausal women with invasive breast cancer who undergo BCT, BMI is an independent prognostic factor for LRR. If confirmed, these findings suggest that more aggressive treatment strategies may be warranted for these women.

Inflammatory breast cancer and development of brain metastases: risk factors and outcomes.

Brain metastases are associated with significant morbidity. Minimal research has been conducted on the risk factors for and incidence of brain metastases in women with inflammatory breast cancer (IBC). 210 women with Stage III or IV IBC diagnosed from 1997-2011 were identified. Competing risk analysis and competing risks regression were used to calculate the incidence of brain metastases and identify significant risk factors. After a median follow-up in surviving patients of 2.8 years (range 0.6-7.6) and 3.3 years (range 0.2-14.5) in the 47 and 163 patients with (MET) and without (non-MET) metastatic disease at diagnosis, 17 (36 %) and 30 (18 %) developed brain metastases, respectively. The cumulative incidence at 1, 2, and 3 years was 17 % [95 % confidence interval (CI), 8-30], 34 % (95 % CI, 20-48), and 37 % (95 % CI, 22-51) for the MET cohort. The corresponding non-MET values were 4 % (95 % CI, 2-8), 8 % (95 % CI 5-13), and 15 % (95 % CI, 10-22). Once non-MET patients developed extracranial distant metastases, the subsequent 1, 2, and 3 years cumulative incidence of brain metastases was 18 % (95 % CI, 10-28), 25 % (95 % CI, 15-36), and 31 % (95 % CI, 20-43). On multivariate analysis, brain metastases were associated with younger age [hazard ratio (HR), 0.73; 95 % CI, 0.53-1.00; P = 0.05] and distant metastases at diagnosis (HR, 2.33; 95 % CI, 1.11-4.89; P = 0.03). The incidence of brain metastases is high in women with IBC. Particularly for patients with extracranial distant metastases, routine screening with magnetic resonance imaging should be considered.

Long-term outcomes among breast cancer patients with extensive regional lymph node involvement: implications for locoregional management.

Extensive lymph node (LN) involvement portends significant risk for distant metastasis (DM) among breast cancer patients. As a result, local management may be of secondary import to systemic control in this population. We analyzed patients with ≥10 involved LNs (N3) to evaluate the feasibility of breast conserving therapy (BCT) vs modified radical mastectomy (MRM) in this high-risk cohort. Among 98 women with N3 disease 46 (46.9%) underwent BCT and 52 (53.1%) received MRM. Nearly all patients (92%) received comprehensive radiotherapy (RT) including axillary and supraclavicular fields. The Kaplan-Meier method and Cox regression analyses were used to analyze time-to-event outcomes. Median follow-up was 76 months, with a 5-year DFS of 64.9% and OS of 71.9% among the cohort. Poorly differentiated (p = 0.007), ER-negative tumors (p = 0.015) had adverse DFS outcomes. Treatment groups did not differ with regard to 10-year DFS (45.4% for MRM vs. 57.6% for BCT; p = 0.31), or OS (61.4 vs. 63.7%; p = 0.79). DM-free survival was 48.9% following MRM and 60.6% following BCT (p = 0.19). Patients with ≥10 involved LNs have similar outcomes following BCT or MRM, suggesting that RT may obviate the need for more-extensive surgery. While local control is comparably favorable regardless of surgical approach, systemic control remains a challenge in this population.

Inflammatory Breast Cancer: Patterns of Failure and the Case for Aggressive Locoregional Management.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive subtype. This study analyzes the patterns of failure in patients with IBC treated at our institution. METHODS: We retrospectively analyzed the records of 227 women with IBC presenting between 1997 and 2011. Survival analysis was used to calculate overall survival (OS) and disease-free survival. Competing risk analysis was used to calculate locoregional recurrence (LRR). RESULTS: A total of 173 patients had locoregional-only disease at presentation (non-MET). Median follow-up in the surviving patients was 3.3 years. Overall, 132 (76.3 %) patients received trimodality therapy with chemotherapy, surgery, and radiotherapy. Three-year OS was 73.1 % [95 % confidence interval (CI) 64.9-82.4]. Cumulative LRR was 10.1, 16.9, and 21.3 % at 1, 2, and 3 years, respectively. No variable was significantly associated with LRR. Fifty-four patients had metastatic disease at presentation (MET). Median follow-up in the surviving patients was 2.6 years. Three-year OS was 44.3 % (95 % CI 31.4-62.5). Twenty-four (44.4 %) patients received non-palliative local therapy (radiotherapy and/or surgery). For these patients, median OS after local therapy was 2 years. Excluding six patients who received local therapy for symptom palliation, the crude incidence of locoregional progression or recurrence (LRPR) was 17 % (4/24) for those who received local therapy compared with 57 % (13/23) for those who did not. CONCLUSIONS: For non-MET patients, LRR remains a problem despite trimodality therapy. More aggressive treatment is warranted. For MET patients, nearly 60 % have LRPR with systemic therapy alone. Local therapy should be considered in the setting of metastatic disease to prevent potential morbidity of progressive local disease.

Ductal Carcinoma In Situ.

In breast cancer (BC) pathogenesis models, normal cells acquire somatic mutations and there is a stepwise progression from high-risk lesions and ductal carcinoma in situ to invasive cancer. The precancer biology of mammary tissue warrants better characterization to understand how different BC subtypes emerge. Primary methods for BC prevention or risk reduction include lifestyle changes, surgery, and chemoprevention. Surgical intervention for BC prevention involves risk-reducing prophylactic mastectomy, typically performed either synchronously with the treatment of a primary tumor or as a bilateral procedure in high-risk women. Chemoprevention with endocrine therapy carries adherence-limiting toxicity.

Should Everyone With Ductal Carcinoma in Situ Receive Adjuvant Radiation?

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

A Phase 1 Dose-Escalation Trial of Radiation Therapy and Concurrent Cisplatin for Stage II and III Triple-Negative Breast Cancer.

PURPOSE: Patients with triple-negative breast cancer (TNBC) experience higher local-regional recurrence rates than those with luminal or HER2-positive tumors. This prospective, phase 1B trial was designed to assess the safety and to establish the maximum tolerated dose (MTD) of cisplatin with radiation therapy for women with early-stage TNBC. METHODS AND MATERIALS: Eligible patients had stage II or III TNBC. Cisplatin was initiated at 10 mg/m2 intravenously once weekly during radiation and then escalated in a 3 + 3 design by 10 mg/m2 at each dose level until 40 mg/m2, or the MTD, was reached. Patients undergoing breast-conserving therapy (BCT) or mastectomy were accrued in separate parallel cohorts during dose escalation, followed by a 10-patient expansion at the MTD. RESULTS: During 2013 to 2018, 55 patients were accrued. Four patients developed dose-limiting toxicity. In the BCT cohort, 1 patient receiving 40 mg/m2 developed tinnitus resulting in a cisplatin delay; therefore, this was the BCT cohort MTD. In the mastectomy cohort, 1 patient receiving 20 mg/m2 developed a grade 3 urinary infection, and 2 additional patients had dose-limiting toxicities at 40 mg/m2 (grade 3 neutropenia and grade 2 tinnitus), both resulting in cisplatin delay. Thus, 30 mg/m2 was the mastectomy cohort MTD. Median follow-up was 48.5 months. Three-year disease-free survival was 74.7% for the BCT cohort and 64.4% for the mastectomy cohort. CONCLUSIONS: Adjuvant radiation therapy with concurrent cisplatin is feasible with a recommended phase 2 dose of 30 mg/m2 and 40 mg/m2 intravenously weekly in mastectomy and BCT cohorts, respectively.

Timing of Lymphedema After Treatment for Breast Cancer: When Are Patients Most At Risk?

PURPOSE: The purpose of the study was to determine when the risk of lymphedema is highest after treatment of breast cancer and which factors influence the time course of lymphedema development. METHODS AND MATERIALS: Between 2005 and 2017, 2171 women (with 2266 at-risk arms) who received surgery for unilateral or bilateral breast cancer at our institution were enrolled. Perometry was used to objectively assess limb volume preoperatively, and lymphedema was defined as a ≥10% relative arm-volume increase arising >3 months postoperatively. Multivariable regression was used to uncover risk factors associated with lymphedema, the Cox proportional hazards model was used to calculate lymphedema incidence, and the semiannual hazard rate of lymphedema was calculated. RESULTS: With a median follow-up of 4 years, the overall estimated 5-year cumulative incidence of lymphedema was 13.7%. Significant factors associated with lymphedema on multivariable analysis were high preoperative body mass index, axillary lymph node dissection (ALND), and regional lymph node radiation (RLNR). Patients receiving ALND with RLNR experienced the highest 5-year rate of lymphedema (31.2%), followed by those receiving ALND without RLNR (24.6%) and sentinel lymph node biopsy with RLNR (12.2%). Overall, the risk of lymphedema peaked between 12 and 30 months postoperatively; however, the time course varied as a function of therapy received. Early-onset lymphedema (<12 months postoperatively) was associated with ALND (HR [hazard ratio], 4.75; P < .0001) but not with RLNR (HR, 1.21; P = .55). In contrast, late-onset lymphedema (>12 months postoperatively) was associated with RLNR (HR, 3.86; P = .0001) and, to a lesser extent, ALND (HR, 1.86; P = .029). The lymphedema risk peaked between 6 and 12 months in the ALND-without-RLNR group, between 18 and 24 months in the ALND-with-RLNR group, and between 36 and 48 months in the group receiving sentinel lymph node biopsy with RLNR. CONCLUSIONS: The time course for lymphedema development depends on the breast cancer treatment received. ALND is associated with early-onset lymphedema, and RLNR is associated with late-onset lymphedema. These results can influence clinical practice to guide lymphedema surveillance strategies and patient education.

Management of the Regional Lymph Nodes in Early-Stage Breast Cancer.

The management of regional nodes in early-stage invasive breast cancer continues to evolve. Improved systemic therapy has contributed to better local regional control, and at the same time it has drawn more attention to its importance. Axillary dissections have decreased, in part because of the increased efficacy of systemic therapy, and also because adjuvant therapy decisions are increasingly driven by biologic characterization of the tumor rather than pathologic nodal information. The trend toward less axillary surgery and a shift toward increased reliance on systemic and radiation therapy to address nodal disease has created interesting questions that were subsequently addressed in recent trials. We review the controversies in regional nodal management, the benefits of current treatment paradigms, the balance between less surgery and more radiation, and the potential tradeoffs vs toxicity.

Analysis of After-Hours Patient Telephone Calls in Two Academic Radiation Oncology Departments: An Opportunity for Improvement in Patient Safety and Quality of Care.

PURPOSE: Patient care within radiation oncology extends beyond the clinic or treatment hours. The on-call radiation oncologist is often not a patient's primary radiation oncologist, introducing the possibility of communication breakdowns and medical errors. This study analyzed after-hours telephone calls to identify opportunities for improved patient safety and quality of care. METHODS AND MATERIALS: Patient calls received outside of business hours between July 1, 2013, and June 30, 2014, at two academic radiation oncology departments were retrospectively reviewed. All calls were analyzed using content analysis, and descriptive analyses were performed. RESULTS: During this time, 5,557 courses of radiotherapy (RT) were delivered. A total of 454 calls were received from 369 unique patients (81%), averaging 4.4 calls per week per department. Phone encounters were documented for 223 calls (49%). The calls were categorized by disease site (No., %): central nervous system (91, 20%), head and neck (78, 17%), genitourinary (53, 12%), GI (52, 12%), thoracic (51, 11%), gynecologic (30, 7%), breast (24, 5%), and other (75, 17%). Patients most often called regarding acute medical, non-RT-related issues (144 calls, 32%); acute RT-related adverse effects (127, 28%); and medication management, including refills (63, 14%). CONCLUSION: This analysis provided novel information regarding the volume of and reasons for after-hours patient-initiated telephone calls. It identified opportunities for actionable improvements in safety and quality of care, particularly with regard to documentation by on-call providers, communication with the primary radiation oncology and extended health care teams, patient education about common RT adverse effects, and medication management.

Radiation therapy risk factors for development of lymphedema in patients treated with regional lymph node irradiation for breast cancer.

PURPOSE: We previously evaluated the risk of breast cancer-related lymphedema (LE) with the addition of regional lymph node irradiation (RLNR) and found an increased risk when RLNR is used. Here we analyze the association of technical radiation therapy (RT) factors in RLNR patients with the risk of LE development. METHODS AND MATERIALS: From 2005 to 2012, we prospectively screened 1476 women for LE who underwent surgery for breast cancer. Among 1507 breasts treated, 172 received RLNR and had complete technical data for analysis. RLNR was delivered as supraclavicular (SC) irradiation (69% [118 of 172 patients]) or SC plus posterior axillary boost (PAB) (31% [54 of 172]). Bilateral arm volume measurements were performed pre- and postoperatively. Patients' RT plans were analyzed for SC field lateral border (relative to the humeral head), total dose to SC, RT fraction size, beam energy, and type of tangent (normal vs wide). Cox proportional hazards models were used to analyze associated risk factors for LE. RESULTS: Median postoperative follow-up was 29.3 months (range: 4.9-74.1 months). The 2-year cumulative incidence of LE was 22% (95% confidence interval [CI]: 15%-32%) for SC and 20% (95% CI: 11%-37%) for SC plus PAB (SC+PAB). None of the analyzed variables was significantly associated with LE risk (extent of humeral head: P=.74 for <1/3 vs >2/3, P=.41 for 1/3 to 2/3 vs >2/3; P=.40 for fraction size of 1.8 Gy vs 2.0 Gy; P=.57 for beam energy 6 MV vs 10 MV; P=.74 for tangent type wide vs regular; P=.66 for SC vs SC+PAB). Only pretreatment body mass index (hazard ratio [HR]: 1.09; 95% CI: 1.04-1.15, P=.0007) and the use of axillary lymph node dissection (HR: 7.08, 95% CI: 0.98-51.40, P=.05) were associated with risk of subsequent LE development. CONCLUSIONS: Of the RT parameters tested, none was associated with an increased risk of LE development. This study underscores the need for future work investigating alternative RLNR risk factors for LE.

Management of the regional lymph nodes following breast-conservation therapy for early-stage breast cancer: an evolving paradigm.

Radiation therapy to the breast following breast conservation surgery has been the standard of care since randomized trials demonstrated equivalent survival compared to mastectomy and improved local control and survival compared to breast conservation surgery alone. Recent controversies regarding adjuvant radiation therapy have included the potential role of additional radiation to the regional lymph nodes. This review summarizes the evolution of regional nodal management focusing on 2 topics: first, the changing paradigm with regard to surgical evaluation of the axilla; second, the role for regional lymph node irradiation and optimal design of treatment fields. Contemporary data reaffirm prior studies showing that complete axillary dissection may not provide additional benefit relative to sentinel lymph node biopsy in select patient populations. Preliminary data also suggest that directed nodal radiation therapy to the supraclavicular and internal mammary lymph nodes may prove beneficial; publication of several studies are awaited to confirm these results and to help define subgroups with the greatest likelihood of benefit.

The impact of radiation therapy on the risk of lymphedema after treatment for breast cancer: a prospective cohort study.

PURPOSE/OBJECTIVE: Lymphedema after breast cancer treatment can be an irreversible condition with a negative impact on quality of life. The goal of this study was to identify radiation therapy-related risk factors for lymphedema. METHODS AND MATERIALS: From 2005 to 2012, we prospectively performed arm volume measurements on 1476 breast cancer patients at our institution using a Perometer. Treating each breast individually, 1099 of 1501 patients (73%) received radiation therapy. Arm measurements were performed preoperatively and postoperatively. Lymphedema was defined as ≥10% arm volume increase occurring >3 months postoperatively. Univariate and multivariate Cox proportional hazard models were used to evaluate risk factors for lymphedema. RESULTS: At a median follow-up time of 25.4 months (range, 3.4-82.6 months), the 2-year cumulative incidence of lymphedema was 6.8%. Cumulative incidence by radiation therapy type was as follows: 3.0% no radiation therapy, 3.1% breast or chest wall alone, 21.9% supraclavicular (SC), and 21.1% SC and posterior axillary boost (PAB). On multivariate analysis, the hazard ratio for regional lymph node radiation (RLNR) (SC ± PAB) was 1.7 (P=.025) compared with breast/chest wall radiation alone. There was no difference in lymphedema risk between SC and SC + PAB (P=.96). Other independent risk factors included early postoperative swelling (P<.0001), higher body mass index (P<.0001), greater number of lymph nodes dissected (P=.018), and axillary lymph node dissection (P=.0001). CONCLUSIONS: In a large cohort of breast cancer patients prospectively screened for lymphedema, RLNR significantly increased the risk of lymphedema compared with breast/chest wall radiation alone. When considering use of RLNR, clinicians should weigh the potential benefit of RLNR for control of disease against the increased risk of lymphedema.

Mini-clinical evaluation exercise as a student assessment tool in a surgery clerkship: lessons learned from a 5-year experience.

BACKGROUND: The mini-clinical evaluation exercise (mini-CEX) used for clinical skill assessment in internal medicine provides in-depth assessment of single clinical encounters. The goals of this study were to determine the feasibility and value of implementation of the mini-CEX in a surgery clerkship. METHODS: Retrospective review of mini-CEX evaluations collected for surgery clerkship students at our institution between 2005 and 2010. Returned assessment forms were tallied. Qualitative feedback comments were analyzed using grounded theory. Principal components analysis identified thematic clusters. Thematic comment counts were compared to those provided via global assessments. RESULTS: For 124 of 137 (90.5%) students, mini-CEX score sheets were available. Thematic clusters identified comments on 8 distinct clinical skill domains. On the mini-CEX, each student received an average of 6.5 ± 2.2 qualitative feedback comments covering 4.5 ± 1.2 separate skills. Of these, 42.7% were critical. Comments provided in global evaluations were fewer (2.9 ± 0.6; P < .001), constrained in scope (0.8 ± 0.2 skills; P < .001), and rarely critical (9.1%). CONCLUSION: A mini-CEX can be incorporated into a surgery clerkship. The number and breadth of feedback comments make the mini-CEX a rich assessment tool. Critical and supportive feedback comments, both highly valuable, are provided nearly equally frequently when the mini-CEX is used as an assessment tool.