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Recent developments in HER2-targeted therapy present new challenges for physicians treating patients with metastatic HER2-positive (HER2+) breast cancer, including how to treat patients with brain metastases, how to properly sequence [...]

Improvements in extracranial disease control and survival of patients with HER2-positive (+) metastatic breast cancer have led to an increased proportion of patients living long enough to develop central nervous [...]

Experimental cell models are indispensable for clarifying the pathophysiology of coronavirus disease 2019 (COVID‐19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, and for developing therapeutic agents. To recapitulate the symptoms and drug response of COVID‐19 patients in vitro, SARS‐CoV‐2 studies using physiologically relevant human embryonic stem (ES)/induced pluripotent stem (iPS) cell‐derived somatic cells and organoids are ongoing. These cells and organoids have been used to show that SARS‐CoV‐2 can infect and damage various organs including the lung, heart, brain, intestinal tract, kidney, and pancreas. They are also being used to develop COVID‐19 therapeutic agents, including evaluation of their antiviral efficacy and safety. The relationship between COVID‐19 aggravation and human genetic backgrounds has been investigated using genetically modified ES/iPS cells and patient‐derived iPS cells. This review summarizes the latest results and issues of SARS‐CoV‐2 research using human ES/iPS cell‐derived somatic cells and organoids. To recapitulate the symptoms and drug response of COVID‐19 patients in vitro, SARS‐CoV‐2 studies using physiologically relevant human embryonic stem/induced pluripotent stem cell‐derived somatic cells and organoids are ongoing. They are being used to investigate SARS‐CoV‐2 cell tropism, to develop COVID‐19 therapeutic agents, and to examine the relationship between COVID‐19 aggravation and human genetic backgrounds.

For breast cancer specialists, much of the excitement at ASCO revolved around the emerging field of checkpoint inhibition in breast cancer and other tumors; however, there were four non-checkpoint presentations [...]

Magee Equations™ (ME) are multivariable models that can estimate oncotypeDX® recurrence score. One of the equations, Magee Equation 3 (ME3) which utilizes only semi-quantitative receptor results has been shown to provide chemopredictive value in the neoadjuvant setting in a single institutional study. This multi-institutional study (seven institutions contributed cases) was undertaken to examine the validity of ME3 in predicting response to neoadjuvant chemotherapy in estrogen receptor positive, HER2-negative breast cancers. Stage IV cases were excluded. The primary endpoint was the pathologic complete response (pCR) rate in different categories of ME3 scores calculated based on receptor results in the pre-therapy core biopsy. A total of 166 cases met the inclusion criteria. The patient age ranged from 24 to 83 years (median 53 years). The average pre-therapy tumor size was 3.9 cm, and axillary lymph nodes were confirmed positive by pre-therapy core biopsy in 85 of 166 cases (51%). The pCR rate according to ME3 scores was 0% (0 of 64) in ME3 < 18, 0% (0 of 46) in ME3 18–25, 14% (3 of 21) in ME3 > 25 to <31, and 40% (14 of 35) in ME3 score 31 or higher (pvalue: <0.0001). There were no distant recurrences and no deaths in the 17 patients with pCR. In the remaining 149 cases with residual disease, ME3 score of >25 was significantly associated with shorter distant recurrence-free survival and showed a trend for shorter breast cancer-specific survival. The results of this multi-institutional study are similar to previously published data from a single institution (PMID: 28548119) and confirm the chemo-predictive value of ME3 in the neoadjuvant setting. In addition, ME3 may provide prognostic information in patients with residual disease which should be further evaluated.

When we consider the use of oral bisphosphonates, intravenous bisphosphonates, or denosumab for early-stage breast cancer, we must ask ourselves two questions. First, do these agents prevent bone loss resulting [...]

Magee Equations™ are multivariable models that can estimate oncotypeDX® Recurrence Score, and Magee Equation 3 has been shown to have chemopredictive value in the neoadjuvant setting as a standalone test. The current study tests the accuracy of Magee Decision Algorithm™ using a large in-house database. According to the algorithm, if all Magee Equation scores are <18, or 18–25 with a mitosis score of 1, then oncotype testing is not required as the actual oncotype recurrence score is expected to be ≤25 (labeled “do not send”). If all Magee Equation scores are 31 or higher, then also oncotype testing is not required as the actual score is expected to be >25 (also “do not send”). All other cases could be considered for testing (labeled “send”). Of the 2196 ER+, HER2-negative cases sent for oncotype testing, 1538 (70%) were classified as “do not send” and 658 (30%) as “send”. The classification accuracy in the “do not send” group was 95.1%. Of the 75 (4.9%) discordant cases (expected score ≤25 by decision algorithm but the actual oncotype score >25), 26 received endocrine therapy alone. None of these 26 patients experienced distant recurrence (average follow-up of 73 months). The Magee Decision Algorithm accurately identifies cases that will not benefit from oncotype testing. Such cases constitute ~70% of the routine clinical oncotype requests, an estimated saving of $300,000 per 100 test requests. The occasional discordant cases (expected ≤25, but actual oncotype score >25) appears to have an excellent outcome on endocrine therapy alone.

IMPORTANCE: A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit. OBJECTIVE: To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone. DESIGN, SETTING, AND PARTICIPANTS: In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor–positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019. INTERVENTIONS: The adjuvant chemotherapy regimen was selected by the treating physician. MAIN OUTCOMES AND MEASURES: Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival [IDFS]). RESULTS: Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error [SE], 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%). CONCLUSIONS AND RELEVANCE: The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00310180

Bone health is a critical issue in the management of women with breast cancer. Many women who develop breast cancer are postmenopausal, which already predisposes them to osteoporosis. Systemic treatments for breast cancer, including chemotherapy and endocrine therapy, decrease circulating levels of estrogen in both pre- and postmenopausal women, further accelerating the natural process of bone loss. The primary concern in breast cancer patients is that this accelerated bone loss, known as cancer treatment-induced bone loss (CTIBL), will lead to an increase in fractures, chronic pain, and loss of mobility. Bisphosphonates are highly effective at slowing the rate of bone loss in postmenopausal women with osteoporosis and at preventing skeletal-related events in women with metastatic breast cancer. Many studies are now focusing on the role of bisphosphonates in preventing CTIBL in the adjuvant setting. Both oral and intravenous bisphosphonates have shown promising activity in preventing CTIBL in patients receiving chemotherapy or hormonal therapy. In addition, emerging data indicate that the use of bisphosphonates in the adjuvant setting may prevent disease recurrence and prolong survival. Data from a number of ongoing trials will further elucidate the role of bisphosphonates in the adjuvant setting over the next few years., Most women with early-stage breast cancer are treated with systemic therapy following surgery in order to prevent disease recurrence. Depending on the individual characteristics of her tumor, a patient may [...]

Metaplastic breast carcinoma is a rare heterogeneous category of breast cancer, often associated with a poor prognosis. Clinical-pathologic studies with respect to varied morphologic subtypes are lacking. There is also a dearth of studies assessing the response of metaplastic breast carcinoma to neoadjuvant chemotherapy. Cases of metaplastic breast carcinoma diagnosed between 2007 and 2017 were identified. Various clinical-pathologic variables were tested for association with survival. Patients who underwent neoadjuvant chemotherapy were assessed for pathologic response. Median age at diagnosis with metaplastic breast carcinoma was 64 years. With a median follow-up of 39 months, 26 patients (27%) recurred (24 distant and 2 loco-regional). The overall survival rate of the cohort was 66% (64/97). A number of variables were associated with survival in univariable analysis; however, in multivariable analysis, only lymph node status and tumor size (pT3 vs. pT1/2) were significantly associated with all survival endpoints: recurrence-free survival, distant recurrence-free survival, overall survival and breast cancer-specific survival. Twenty-nine of 97 (30%) patients with metaplastic breast carcinoma received neoadjuvant chemotherapy. Five (17%) patients achieved pathologic complete response. Matrix-producing morphology was associated with higher probability of achieving pathologic complete response (p= 0.027). Similar to other breast cancer subtypes, tumor size and lymph node status are prognostic in metaplastic carcinomas. The pathologic complete response rate of metaplastic breast carcinoma in our cohort was 17%, higher than previously reported. Although the matrix-producing subtype was associated with pathologic complete response, there was no survival difference with respect to tumor subtypes.

Magee Equations were derived as an inexpensive, rapid alternative to Oncotype DX. The Magee Equation 3 utilizes immunohistochemical and FISH data for estrogen receptor (ER), progesterone receptor (PR), HER2 and Ki-67 for its calculation (24.30812+ERIHC × (−0.02177)+PRIHC × (−0.02884)+(0 for HER2 negative, 1.46495 for equivocal, 12.75525 for HER2 positive)+Ki-67 × 0.18649). We hypothesize that Magee Equation 3 scores from pre-therapy core biopsy can predict response to neoadjuvant systemic chemotherapy. A prospectively-maintained database of patients who received neoadjuvant systemic therapy from 2010 to 2014 at a single institution was retrospectively reviewed. Pathologic complete response was defined as absence of invasive tumor in the breast and regional lymph nodes. Of the 614 cases, tumors with missing immunohistochemical results and those that were ER negative or HER2 positive were excluded. This resulted in 237 ER positive, HER2 negative/equivocal tumors that formed the basis of this study. Magee Equation 3 scores were divided into 3 categories similar to Oncotype DX, ie, 0 to <18 (low), 18 to <31 (intermediate), and 31 or higher (high) scores. The pathologic complete response rate for low, intermediate and high Magee Equation 3 scores was 0%, 4%, and 36%, respectively. Patients with high Magee Equation 3 scores were 13 times more likely to achieve pathologic complete response compared to those with Magee Equation 3 scores less than 31 (95% CI 5.09–32.87, P<0.0001). For patients that did not achieve pathologic complete response, high Magee Equation 3 correlated with higher recurrence rate, with the majority occurring in patients with positive lymph nodes in the resection specimen. Magee Equation 3 score ≥31 predicts pathologic complete response in the neoadjuvant setting and for tumor recurrence, when pathologic complete response is not achieved. These results show the utility of Magee Equation 3 in predicting patients who will benefit from chemotherapy but warrant prospective multi-institutional validation.

Supplemental Digital Content is available in the text.Women with advanced breast carcinomas have few therapeutic options. Recent advances in genomic profiling represent a new paradigm of cancer classification and treatment, but experience with genomic testing in a clinical setting remains limited. We retrospectively determined the genomic variants and correlate these with histology [histomorphologic subtype, nuclear grade, standard immunohistochemistry (IHC)] and clinical utilization (ordering, turnaround time, report review, and targeted therapy). Among 48 patients, 2 showed no genetic alterations, 11 (23%) showed variants of unclear significance only and 35 (73%) showed variant(s) affecting function (VaF) and/or variants of unclear significance. Overall, 119 variants were observed in 20 of 50 tested genes. Each patient had a unique molecular profile, with numerous (n=58) variants not previously reported in breast cancer. VaF detected in more than 2 patients included: TP53(n=21), PIK3CA(n=20), and FGFR1(n=3). VaF comprised 46 single nucleotide variants (79%), 7 amplifications (12%), 3 frameshifts (5%), 1 insertion (2%), and 1 deletion (2%). The tested samples had very high Ki67 index (average 57%±23%) and approximately half were hormone receptor and HER2 negative (25/46, 54%). Metastatic breast carcinomas showed a higher average VaF versus breast-localized tumors (1.3±0.99 vs. 0.18±0.60, P<0.05). Next-generation sequencing reports were promptly reported and reviewed (average 1 to 2 d) and 7 (∼25%) of potentially eligible patients received targeted therapy. Advanced breast cancers show unique landscapes of genetic variants. Most testing was done in late disease, often in metastatic and receptor-negative carcinomas. Next-generation sequencing results were promptly reported and reviewed, but the utilization of targeted therapies was limited.

IMPORTANCE: Patients with breast cancer (BrCa) brain metastases (BrM) have limited therapeutic options. A better understanding of molecular alterations acquired in BrM could identify clinically actionable metastatic dependencies. OBJECTIVE: To determine whether there are intrinsic subtype differences between primary tumors and matched BrM and to uncover BrM-acquired alterations that are clinically actionable. DESIGN, SETTING, AND PARTICIPANTS: In total, 20 cases of primary breast cancer tissue and resected BrM (10 estrogen receptor [ER]-negative and 10 ER-positive) from 2 academic institutions were included. Eligible cases in the discovery cohort harbored patient-matched primary breast cancer tissue and resected BrM. Given the rarity of patient-matched samples, no exclusion criteria were enacted. Two validation sequencing cohorts were used—a published data set of 17 patient-matched cases of BrM and a cohort of 7884 BrCa tumors enriched for metastatic samples. MAIN OUTCOMES AND MEASURES: Brain metastases expression changes in 127 genes within BrCa signatures, PAM50 assignments, and ERBB2/HER2 DNA-level gains. RESULTS: Overall, 17 of 20 BrM retained the PAM50 subtype of the primary BrCa. Despite this concordance, 17 of 20 BrM harbored expression changes (&lt;2-fold or >2-fold) in clinically actionable genes including gains of FGFR4 (n = 6 [30%]), FLT1 (n = 4 [20%]), AURKA (n = 2 [10%]) and loss of ESR1 expression (n = 9 [45%]). The most recurrent expression gain was ERBB2/HER2, which showed a greater than 2-fold expression increase in 7 of 20 BrM (35%). Three of these 7 cases were ERBB2/HER2-negative out of 13 ERBB2/HER2-negative in the primary BrCa cohort and became immunohistochemical positive (3+) in the paired BrM with metastasis-specific amplification of the ERBB2/HER2 locus. In an independent data set, 2 of 9 (22.2%) ERBB2/HER2-negative BrCa switched to ERBB2/HER2-positive with 1 BrM acquiring ERBB2/HER2 amplification and the other showing metastatic enrichment of the activating V777L ERBB2/HER2 mutation. An expanded cohort revealed that ERBB2/HER2 amplification and/or mutation frequency was unchanged between local disease and metastases across all sites; however, a significant enrichment was appreciated for BrM (13% local vs 24% BrM; P &lt; .001). CONCLUSIONS AND RELEVANCE: Breast cancer BrM commonly acquire alterations in clinically actionable genes, with metastasis-acquired ERBB2/HER2 alterations in approximately 20% of ERBB2/HER2-negative cases. These observations have immediate clinical implications for patients with ERBB2/HER2–negative breast cancer and support comprehensive profiling of metastases to inform clinical care.

Aim:The Make Your Dialogue Count survey aimed to explore communication gaps between patients/caregivers and oncologists, and the needs of patients/caregivers at diagnosis and most recent treatment change. Methods:Three distinct sets of parallel questions were asked of 359 women with metastatic breast cancer, 234 caregivers and 252 oncologists. Survey respondents were not necessarily associated with each other. Results:Patients/caregivers considered themselves knowledgeable, yet many lacked basic disease information affecting treatment decisions. Patients/caregivers reported that oncologists do not discuss important topics at diagnosis. Patients failed to discuss side effects, but wanted their oncologist’s help to manage side effects. Conclusion:This survey provides additional insight on interactional dynamics to bridge gaps in understanding that affect quality of care.

The NSABP B-35 trial compared 5 years of treatment with anastrozole versus tamoxifen for reducing subsequent occurrence of breast cancer in postmenopausal patients with ductal carcinoma in situ. This report assesses the effect of these drugs on quality of life and symptoms.

Ductal carcinoma in situ is currently managed with excision, radiotherapy, and adjuvant hormone therapy, usually tamoxifen. We postulated that an aromatase inhibitor would be safer and more effective. We therefore undertook this trial to compare anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy.

Oral hyperpigmentation is an infrequent phenomenon reported in the literature as a side effect that may be seen with the administration of certain chemotherapy agents such as doxorubicin. Given the under reported nature of mucosal hyperpigmentation, treating providers are frequently unaware of this benign presentation and thus may pursue unnecessary testing. The exact pathophysiology and mechanism of action of this phenomenon is poorly understood; however, it is hypothesized that some chemotherapy drugs may trigger increased melanin deposition. With regard to management, clinical monitoring for eventual resolution status post chemotherapy without additional therapy is sufficient. Increased familiarity with this uncommon side effect will prevent invasive testing and undue stress to the patient. We present a case of tongue hyperpigmentation that occurred during administration of doxorubicin and cyclophosphamide in the neoadjuvant setting for management of stage IIIA(cT2,cN1,M0) hormone receptor positive breast cancer, which resolved without intervention after completion of chemotherapy course.

Women with breast cancer have been found to have poorer cognitive function before the initiation of systemic adjuvant therapy than their age- and education-matched counterparts. The basis for this may partly include hormone exposure during the course of a woman’s life.

Oncotype DX is a commercial assay frequently used for making chemotherapy decisions in estrogen receptor (ER)-positive breast cancers. The result is reported as a recurrence score ranging from 0 to 100, divided into low-risk (<18), intermediate-risk (18–30), and high-risk (≥31) categories. Our pilot study showed that recurrence score can be predicted by an equation incorporating standard morphoimmunohistologic variables (referred to as original Magee equation). Using a data set of 817 cases, we formulated three additional equations (referred to as new Magee equations 1, 2, and 3) to predict the recurrence score category for an independent set of 255 cases. The concordance between the risk category of Oncotype DX and our equations was 54.3%, 55.8%, 59.4%, and 54.4% for original Magee equation, new Magee equations 1, 2, and 3, respectively. When the intermediate category was eliminated, the concordance increased to 96.9%, 100%, 98.6%, and 98.7% for original Magee equation, new Magee equations 1, 2, and 3, respectively. Even when the estimated recurrence score fell in the intermediate category with any of the equations, the actual recurrence score was either intermediate or low in more than 80% of the cases. Any of the four equations can be used to estimate the recurrence score depending on available data. If the estimated recurrence score is clearly high or low, the oncologists should not expect a dramatically different result from Oncotype DX, and the Oncotype DX test may not be needed. Conversely, an Oncotype DX result that is dramatically different from what is expected based on standard morphoimmunohistologic variables should be thoroughly investigated.

OncotypeDX is a commercial assay frequently used for making chemotherapy decisions in estrogen receptor (ER)-positive breast cancers. The result is reported as a recurrence score ranging from 0 to 100, divided into low-risk (<18), intermediate-risk (18–30), and high-risk (≥31) categories. Our pilot study showed that recurrence score can be predicted by an equation incorporating standard morphoimmunohistologic variables (referred to as original Magee equation). Using a data set of 817 cases, we formulated three additional equations (referred to as new Magee equations 1, 2, and 3) to predict the recurrence score category for an independent set of 255 cases. The concordance between the risk category of OncotypeDX and our equations was 54.3%, 55.8%, 59.4%, and 54.4% for original Magee equation, new Magee equations 1, 2, and 3, respectively. When the intermediate category was eliminated, the concordance increased to 96.9%, 100%, 98.6%, and 98.7% for original Magee equation, new Magee equations 1, 2, and 3, respectively. Even when the estimated recurrence score fell in the intermediate category with any of the equations, the actual recurrence score was either intermediate or low in more than 80% of the cases. Any of the four equations can be used to estimate the recurrence score depending on available data. If the estimated recurrence score is clearly high or low, the oncologists should not expect a dramatically different result from OncotypeDX, and the OncotypeDX test may not be needed. Conversely, an OncotypeDX result that is dramatically different from what is expected based on standard morphoimmunohistologic variables should be thoroughly investigated.

Estrogen receptor (ER) signaling plays a critical role in many breast cancers. As a result, endocrine therapy is a mainstay in the treatment plan for patients with hormone receptor-positive breast cancer. Although patients with metastatic breast cancer (MBC) are often given several lines of endocrine therapy throughout the course of their disease, the optimal sequence of and exact mechanisms of resistance to endocrine therapy remain unclear. Endocrine therapies include aromatase inhibitors, selective ER modulators, and selective ER downregulators. These agents interfere with ER signaling and inhibit breast cancer growth, but their mechanisms of action (MOAs) are distinct and potential mechanisms of resistance vary. Patient-specific factors (eg, tumor characteristics, burden of disease, patient preferences, and treatment history) and the MOAs of the available agents are important considerations. This review discusses the latest understanding of ER biology, the mechanistic differences between endocrine therapies, and future directions in endocrine therapy for MBC.

Pathologic complete response to neoadjuvant chemotherapy without trastuzumab in hormone receptor-negative/HER2+ tumors is seen in 27–45% of cases. In contrast, estrogen receptor (ER)+/HER2+ tumors demonstrate pathologic complete response in ∼8% of cases and is generally limited to weak-to-moderate ER+/HER2+ tumors. It is speculated that addition of trastuzumab to neoadjuvant chemotherapy regimen will increase the pathologic complete response rates in all HER2+ tumors. A list of HER2+ patients who received neoadjuvant chemotherapy (with trastuzumab) in the years 2007–2010 was obtained from our hospital database. The 104 HER2+ tumors were classified into three groups based on semiquantitative hormone receptor and HER2 results as follows: ERBB2 (ER–/PR–[H-score ≤10]/HER2+), Luminal B-HER2 Hybrid (LBHH; weak to moderate ER+ [H-score 11–199]/HER2+), and Luminal A-HER2 Hybrid (LAHH; strong ER+[H-score ≥200]/HER2+). Pathologic complete response was defined as absence of invasive carcinoma in the resection specimen and in the lymph nodes. Percentage tumor volume reduction was also calculated based on pretherapy size and detailed evaluation of the resection specimen. In all, 52% (25 of 48 cases) of ERBB2 tumors showed pathologic complete response, which was significantly higher than the pathologic complete response rate in LBHH (33%; 10 of 30) and LAHH (8%; 2 of 26) tumors. Average percentage tumor volume reduction was also highest in ERBB2 tumors (86%), followed by LBHH (74%) and LAHH (64%) tumors. We conclude that addition of trastuzumab to neoadjuvant chemotherapy regimen significantly increases the pathologic complete response rates in all HER2+ tumors. However, the benefit of trastuzumab is highest in ER-negative tumors and progressively decreases with increase in tumor ER expression. This information can be utilized to counsel patients considered for neoadjuvant chemotherapy and the same principle could be applied in the adjuvant setting.

Background:A variety of markers have been proposed to identify breast cancer stem cells. Here, we used immunohistostaining and flow cytometry to analyze their interrelationships and to sort cells for tumorigenicity studies.Methods:Cytokeratin, CD44, and CD90 were localized to primary breast cancer and normal breast NB tissue by immunohistostaining and related to CD117 and CD133 expression by flow cytometry. Immunodeficient NOD.CB17PrkdcscidJ and NOD.CgPrkdcscidIl2rgtm1WjlSzJ mice were used to test tumorigenicity of sorted CD90 lowlight scatter, CD90 highlight scatter, and CD90negtumor cells.Results:NB basal cells coexpressed CD44 and CD90. As cells transited luminally, CD44 was retained and downmodulated, and CD90 was lost and cytokeratin increased. In breast tumors, basallike CD44CD90 cells were localized to the tumor periphery, adjacent to CD90 stroma. Like normal luminal cells, interior tumor cells were CD44CD90−. Immunophenotyping CD44CD90CD117CD133 of cytokeratin cells revealed no significant difference in expression between tumors and tumorfree breast. In both, CD133 was distributed approximately equally among CD44CD90 subsets, whereas CD117 expression was highest in the basalassociated CD44CD90 subset. Sorted CD90 pleural effusion cells with lymphoid light scatter, 49 of which were CD44, were uniquely tumorigenic in immunodeficient mice 100 cellsinjection.Conclusions:Our data demonstrate that all tumors contain a small population of CD44CD90 cells, mimicking the phenotype of ductalbasal cells. These are localized to the tumor periphery, adjacent to CD90 stroma. Among the nonhematopoietic, nonmesothelial cells found in metastatic pleural effusions, lowlight scatter CD90 cells are most potently tumorigenic, compared to highscatter CD90 cells and CD90− cells. © 2010 International Clinical Cytometry Society

Patients with breast cancer (BC) experience bone loss as a result of either cancer treatment or metastatic disease to the bone. In addition, baseline factors universally associated with bone loss have been identified, including history of fracture, menopausal status, oral corticosteroid use, osteoporosis, and smoking. Whereas treatment effects causing suppression of estrogen function or estrogen-deprivation are the predominant cause of bone loss and fractures among patients with earlier-stage disease, metastatic lesions to the bone are the principal drivers of bone loss and associated skeletal complications in patients with advanced disease. Development of fractures and other skeletal-related events (SREs) is associated with adverse clinical outcome. Several studies clearly have demonstrated the efficacy of bisphosphonates (BPs) in the metastatic setting. Recently, the targeted agent denosumab also demonstrated favorable efficacy in preventing SREs in this setting. In addition, clinical evidence has demonstrated that zoledronic acid (ZOL) can prevent bone loss and may provide an anticancer benefit in earlier-stage breast disease, supporting the potential use of early/concomitant intervention with BP therapy in the adjuvant setting. Overall, these data warrant further consideration of the role of bisphosphonates in BC. Ongoing studies will further investigate the bone-protective and potential anticancer benefits of BPs across all stages of breast disease.

Postmenopausal women with breast cancer receiving adjuvant aromatase inhibitors (AIs) are at risk for accelerated bone loss and subsequent fractures. The ongoing Zometa-Femara Adjuvant Synergy Trial (Z-FAST) is evaluating the efficacy and safety of zoledronic acid in preventing such bone loss.

Third-generation aromatase inhibitors (AIs; anastrozole, letrozole, exemestane) have replaced tamoxifen as the adjuvant treatment of choice for postmenopausal women with hormone receptor–positive early-stage breast cancer. Because bone loss is a predictable adverse event of AI therapy, early recognition, prevention, and/or treatment of AI-induced bone loss is needed. One to 5 years of AI therapy causes a bone mineral density (BMD) loss of up to 7.2% in postmenopausal women; however, current clinical guidelines do not recommend initiating bisphosphonate therapy for the treatment of BMD loss until fragility fractures or frank osteoporosis occur. Results of recent trials evaluating the use of intravenous (I.V.) zoledronic acid as prevention and treatment of AI-induced bone loss in women with early-stage breast cancer receiving letrozole suggest a potential benefit to the concurrent use of zoledronic acid and letrozole. To our knowledge, clinical trials assessing oral or other I.V. bisphosphonates for these indications have not been published. Recently, concerns of bisphosphonate-induced renal safety and osteonecrosis of the jaw have emerged. Studies evaluating bisphosphonates in women with breast cancer have reported lower rates of renal dysfunction than those reported in patients with metastatic cancer receiving bisphosphonates, and no cases of jaw osteonecrosis. The use of bisphosphonates in this population requires further study to more clearly define the most appropriate timing and length of therapy as well as the long-term efficacy and safety of these drugs. Until these data become available, balancing the safety concerns with the potential benefits of I.V. bisphosphonates to minimize or prevent AI-induced bone loss in women with early-stage breast cancer is required.

Oncotype DX™ is a commercially available reverse transcriptase-polymerase chain reaction based assay that provides a Recurrence Score (RS) and has been shown to provide prognostic and predictive information in estrogen receptor-positive lymph node-negative breast cancers. Independent studies of its utility in routine practice are lacking. Slides and surgical pathology reports from 42 cases of breast carcinomas evaluated by Oncotype DX™ were retrospectively reviewed to determine patient age, tumor size, histologic grade, estrogen and progesterone receptor (ER and PR) and ERBB2 (HER-2/neu) data, with ER and PR reported as a semi-quantitative score reflecting both intensity of staining and proportion of positive cells. We show here that Recurrence Score is significantly correlated with tubule formation, nuclear grade, mitotic count, ER immunohistochemical score, PR immunohistochemical score, and HER-2/neu status, and that the equation RS=13.424+5.420 (nuclear grade) +5.538 (mitotic count) −0.045 (ER immunohistochemical score) −0.030 (PR immunohistochemical score) +9.486 (HER-2/neu) predicts the Recurrence Score with an R2of 0.66, indicating that the full model accounts for 66% of the data variability. Although the Oncotype DX™ Recurrence Score holds potential, further validation of its independent value beyond that of histopathologic analysis is necessary before it can be implemented in clinical decision making.Modern Pathology (2008) 21, 1255–1261; doi:10.1038/modpathol.2008.54; published online 21 March 2008

OncotypeDX™ is a commercially available reverse transcriptase-polymerase chain reaction based assay that provides a Recurrence Score (RS) and has been shown to provide prognostic and predictive information in estrogen receptor-positive lymph node-negative breast cancers. Independent studies of its utility in routine practice are lacking. Slides and surgical pathology reports from 42 cases of breast carcinomas evaluated by OncotypeDX™ were retrospectively reviewed to determine patient age, tumor size, histologic grade, estrogen and progesterone receptor (ER and PR) and ERBB2 (HER-2/neu) data, with ER and PR reported as a semi-quantitative score reflecting both intensity of staining and proportion of positive cells. We show here that Recurrence Score is significantly correlated with tubule formation, nuclear grade, mitotic count, ER immunohistochemical score, PR immunohistochemical score, and HER-2/neu status, and that the equation RS=13.424+5.420 (nuclear grade) +5.538 (mitotic count) −0.045 (ER immunohistochemical score) −0.030 (PR immunohistochemical score) +9.486 (HER-2/neu) predicts the Recurrence Score with an R2of 0.66, indicating that the full model accounts for 66% of the data variability. Although the OncotypeDX™ Recurrence Score holds potential, further validation of its independent value beyond that of histopathologic analysis is necessary before it can be implemented in clinical decision making.

Background: Cancer therapy-induced bone loss (CTIBL) and bone loss in postmenopausal (PMW) increase fracture risk. Objective: To review the efficacy and safety of zoledronic acid (ZA) for prevention and treatment of CTIBL and postmenopausal bone loss. Methods: Using PubMed, a search of the English language literature (January 1950 to November 2007) was performed to identify articles evaluating ZA in CTIBL patients without bone metastases and for postmenopausal bone loss; articles were reviewed and evaluated. Results/conclusion: Intermittent administration of ZA increases BMD, decreases bone turnover markers, and is well tolerated in both cancer patients without bone metastases and osteopenic/osteoporotic PMW. In osteopenic/osteoporotic PMW, ZA also decreases fracture rates and prevents second fractures. The optimal regimens in these populations are unknown.

Hormones have been implicated as modulators of cognitive functioning. For instance, results of our previous work in women with breast cancer showed that cognitive impairment was more severe and involved more memory domains in those who received adjuvant tamoxifen therapy compared with women who received chemotherapy alone or no adjuvant therapy. Recently aromatase inhibitors such as anastrozole have been used in lieu of tamoxifen for the adjuvant treatment of postmenopausal women with hormone receptor-positive, early-stage breast cancer. Plasma estrogen levels are significantly lower in women who receive anastrozole compared with those who receive tamoxifen. We hypothesized, therefore, that anastrozole would have a more profound effect on cognitive function than tamoxifen, a mixed estrogen agonist/antagonist.

The purpose of this study was to evaluate the combination of docetaxel plus vinorelbine as neoadjuvant chemotherapy for stage II/III locally advanced breast cancer.

IMPORTANCE: Overtreatment of early-stage breast cancer with favorable tumor biology in older patients may be harmful without affecting recurrence and survival. Guidelines that recommend deimplementation of sentinel lymph node biopsy (SLNB) (Choosing Wisely) and radiotherapy (RT) (National Comprehensive Cancer Network) have been published. OBJECTIVE: To describe the use rates and association with disease recurrence of SLNB and RT in older women with breast cancer. DESIGN, SETTING, AND PARTICIPANTS: This cohort study obtained patient and clinical data from an integrated cancer registry and electronic health record of a single health care system in Pennsylvania. The cohort was composed of consecutive female patients 70 years or older who were diagnosed with early-stage, estrogen receptor–positive, ERBB2 (formerly HER2)–negative, clinically node-negative breast cancer from January 1, 2010, to December 31, 2018, who were treated at 15 community and academic hospitals within the health system. EXPOSURES: Sentinel lymph node biopsy and adjuvant RT. MAIN OUTCOMES AND MEASURES: Primary outcomes were 5-year locoregional recurrence-free survival (LRFS) rate and disease-free survival (DFS) rate after SLNB and after RT. Secondary outcomes included recurrence rate, subgroups that may benefit from SLNB or RT, and use rate of SLNB and RT over time. Propensity scores were used to create 2 cohorts to separately evaluate the association of SLNB and RT with recurrence outcomes. Cox proportional hazards regression model was used to estimate hazard ratios (HRs). RESULTS: From 2010 to 2018, a total of 3361 women 70 years or older (median [interquartile range {IQR}] age, 77.0 [73.0-82.0] years) with estrogen receptor–positive, ERBB2-negative, clinically node-negative breast cancer were included in the study. Of these women, 2195 (65.3%) received SLNB and 1828 (54.4%) received adjuvant RT. Rates of SLNB steadily increased (1.0% per year), a trend that persisted after the 2016 adoption of the Choosing Wisely guideline. Rates of RT decreased slightly (3.4% per year). To examine patient outcomes and maximize follow-up time, the analysis was limited to cases from 2010 to 2014, identifying 2109 patients with a median (IQR) follow-up time of 4.1 (2.5-5.7) years. In the propensity score–matched cohorts, no association was found between SLNB and either LRFS (HR, 1.26; 95% CI, 0.37-4.30; P?=?.71) or DFS (HR, 1.92; 95% CI, 0.86-4.32; P?=?.11). In addition, RT was not associated with LRFS (HR, 0.33; 95% CI, 0.09-1.24; P?=?.10) or DFS (HR, 0.99; 95% CI, 0.46-2.10; P?=?.97). Subgroup analysis showed that stratification by tumor grade or comorbidity was not associated with LRFS or DFS. Low absolute rates of recurrence were observed when comparing the groups that received SLNB (3.5%) and those that did not (4.5%) as well as the groups that received RT (2.7%) and those that did not (5.5%). CONCLUSIONS AND RELEVANCE: This study found that receipt of SLNB or RT was not associated with improved LRFS or DFS in older patients with ER-positive, clinically node-negative breast cancer. Despite limited follow-up time and wide 95% CIs, this study supports the continued deimplementation of both SLNB and RT in accordance with the Choosing Wisely and National Comprehensive Cancer Network guidelines.

In this issue of Cell Reports, Li et al. show that the analysis of genetic changes in patient-derived xenografts can reveal crucial details of tumor evolution, such as the emergence of functional estrogen receptor mutations in endocrine-resistant breast cancer.

Neoadjuvant chemotherapy can increase the rates of breast-conserving surgery in patients with operable breast cancer and is a reasonable alternative to adjuvant chemotherapy. Several trials have shown that adding bevacizumab (an antiangiogenic monoclonal antibody against vascular endothelial growth factor A) and the antimetabolites capecitabine and gemcitabine to taxanes can improve outcomes in patients with metastatic breast cancer.