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Inflammatory breast cancer (IBC) is a rare variety of breast cancer accounting for two percent of breast cancer diagnoses in the United States. It is characterized by peau d’orange, breast edema and erythema on physical examination and dermal lymphatic invasion by tumor emboli on histological examination. Micrometastases to lymphatics and bone marrow at the time of diagnosis and angiogenic properties of IBC explain the high propensity of this cancer to relapse and metastasize, its aggressiveness and poor prognosis. Preoperative sequential anthracycline and taxane (plus trastuzumab and pertuzumab if HER2-positive) based chemotherapy is the current standard of care for IBC. We herein report a case of stage IIIC triple-negative IBC treated with pembrolizumab plus chemotherapy based neoadjuvant therapy with a complete clinical and complete pathological response. This is the first case of triple-negative IBC treated with this regimen reported in the literature, thereby providing clinical data on the tolerability and efficacy of pembrolizumab plus chemotherapy based neoadjuvant regimen for the treatment of IBC.

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.

Multinucleated H2B-RFP Tub-GFP MDA-MB-231 Multipolar Division

Mononucleated H2B-RFP Tub-GFP MDA-MB-231 Bipolar Division

Purpose:As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings.Patients and Methods:In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1–2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination.Results:The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8–38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2–31.1) for stratum 2 (n = 101). Patients with PD-L1–positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1–negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9–54.3) vs 16.1% (95% CI: 5.5–33.7); stratum 2, 24.4% (95% CI: 12.9–39.5) vs 18.2% (95% CI: 8.2–32.7)].Conclusions:Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.

Supplementary Information

Triple-negative breast cancer (TNBC) commonly develops resistance to chemotherapy, yet markers predictive of chemoresistance in this disease are lacking. Here, we define WNT10B-dependent biomarkers for β-CATENIN/HMGA2/EZH2 signaling predictive of reduced relapse-free survival. Concordant expression of HMGA2 and EZH2 proteins is observed in MMTV-Wnt10bLacZ transgenic mice during metastasis, and Hmga2 haploinsufficiency decreased EZH2 protein expression, repressing lung metastasis. A novel autoregulatory loop interdependent on HMGA2 and EZH2 expression is essential for β-CATENIN/TCF-4/LEF-1 transcription. Mechanistically, both HMGA2 and EZH2 displaced Groucho/TLE1 from TCF-4 and served as gatekeepers for K49 acetylation on β-CATENIN, which is essential for transcription. In addition, we discovered that HMGA2-EZH2 interacts with the PRC2 complex. Absence of HMGA2 or EZH2 expression or chemical inhibition of Wnt signaling in a chemoresistant patient-derived xenograft (PDX) model of TNBC abolished visceral metastasis, repressing AXIN2, MYC, EZH2, and HMGA2 expression in vivo. Combinatorial therapy of a WNT inhibitor with doxorubicin synergistically activated apoptosis in vitro, resensitized PDX-derived cells to doxorubicin, and repressed lung metastasis in vivo. We propose that targeting the WNT10B biomarker network will provide improved outcomes for TNBC.Significance:These findings reveal targeting the WNT signaling pathway as a potential therapeutic strategy in triple-negative breast cancer.

Supplementary Section: 1) Seven supplementary figures and legends: A. Supplementary figure S1: TCGA analysis of WNT10B network. B. Supplementary figure S2: Human IHC analysis of WNT10B, HMGA2 and EZH2. C. Supplementary figure S3: Mouse IHC analysis of HMGA2 and EZH2. D. Supplementary figure S4: ChIP, qPCR and IB analysis on WNT10B/�CATENIN direct target genes. E. Supplementary figure S5: Characterization of CRISPR HMGA2KO and EZH2KO cells both in vitro and in vivo. F. Supplementary figure S6: Validation of WNT10B network on TNBC PDX tumors. G. Supplementary figure S7: Isobologram curves of ICG-001 and Doxorubicin activity. 2) Supplementary Material & Methods 3) Supplementary Table 1 (ST1) qPCR primers 4) Supplementary Table 2 (ST2) ChIP primers 5) 6) Supplementary Table 3 (ST3) drug combinatorial index

Supplementary Figure Legends 1-2 from Bidirectional Crosstalk between Leptin and Insulin-like Growth Factor-I Signaling Promotes Invasion and Migration of Breast Cancer Cells via Transactivation of Epidermal Growth Factor Receptor

Supplementary Figure 1 from Bidirectional Crosstalk between Leptin and Insulin-like Growth Factor-I Signaling Promotes Invasion and Migration of Breast Cancer Cells via Transactivation of Epidermal Growth Factor Receptor

Fig. S1. Supplementary data for large scale genomic aberrations illustrated in Figure 2, including: A) the distribution of mapped read density of WGS; B) PCR confirmation of translocation and fusion junctions of a superamplicon; and C) PCR and RT-PCR amplification of MGAM, ZFAND3, and the ZFAND3-MGAM fusion gene. Fig. S2. The distribution of mapped read density of WES, supplementary data for Figure 3. Fig. S3. Differentially expressed genes and functions among complex, simple carcinomas and normal mammary glands, supplementary data for Figure 3. Fig. S4. IHC images of histone modifications in canine normal mammary glands at 400X magnification, supplementary data for Figure 4. Fig. S5. IHC images of histone modifications in simple carcinomas, complex carcinomas and normal mammary glands at 200X magnification, supplementary data for Figure 5. Fig. S6. Supplementary data for homology between canine MCs and human breast cancers described in Figure 6. These include differentially expressed genes between ER+ and ER- carcinomas at FDR ≤ 0.1 and an example of PAM50 clustering indicating canine and human tumor IDs.

Supplementary Figure 2 from Bidirectional Crosstalk between Leptin and Insulin-like Growth Factor-I Signaling Promotes Invasion and Migration of Breast Cancer Cells via Transactivation of Epidermal Growth Factor Receptor

The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has dramatically improved outcomes for patients with metastatic, hormone receptor (HR)-positive breast cancer. Because of the continued high rate of relapse in patients with node-positive, HR-positive disease, evaluating these agents in the adjuvant setting is the logical next step. Three adjuvant CDK inhibitor trials have been reported to date, with only 1 of them showing a statistical advantage for the CDK inhibitor in comparison with endocrine therapy alone. These trials have key similarities and differences that could explain the disparate results. The one positive trial has a relatively short follow-up, and continued analysis is critical to confirm the benefit of adjuvant CDK inhibition in this setting. It is imperative that predictive biomarkers be determined so that these agents can be used in the patients most likely to benefit and thus the additional toxicity and expense can be avoided in those who do not require these agents. LAY SUMMARY: There is a critical need for new agents to prevent relapse in patients with hormone receptor-positive breast cancer. Trials to date evaluating cyclin-dependent kinase inhibitors, which decrease how quickly cancer cells multiply, have shown mixed results, with only 1 trial demonstrating that these agents decrease recurrence.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.

Triple negative breast cancer (TNBC) represents 15% to 20% of all primary breast cancers and is the most aggressive subtype of breast cancer. There has been rapid progress in targeted therapy and biomarker development to identify the optimal treatments for TNBC. To update recent developments, this article comprehensively reviews molecular classification and biomarkers of TNBC and targeted therapy developments in immunotherapy, PARP and AKT pathway inhibitors, antibody-drug conjugates and androgen receptor blockade. The treatment of TNBC has dramatically evolved beyond basic cytotoxic chemotherapy into an expanding domain of targeted therapies tailored to the heterogeneity of this complex and aggressive disease. Progress will continue through the sustained and devoted efforts of our investigators and the patients who dedicatedly enroll in clinical trials. Through a daring persistence to challenge the status quo we now have the opportunity to offer our patients with TNBC a new sense of hope.

Background: Phosphatidylinositol-3-kinase (PI3K) activating mutations are found in 30-40% of breast cancers, and the PI3K inhibitor alpelisib is FDA-approved for PIK3CA-mutated hormone-receptor positive metastatic breast cancer (MBC). However, rates of intrinsic alpelisib resistance are as high as 40%, and there is an ongoing need for novel biomarkers to help guide patient selection. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) may better reflect the heterogeneity of metastatic disease than tissue biopsy, and are amenable to longitudinal analysis. By combining targeted ctDNA sequencing with CTC transcriptional profiling and quantitation of PI3K pathway phospho-proteins, we have developed the first multiplex assay to simultaneously assess genomic alterations and CTC PI3K pathway activity via liquid biopsy. Methods: Peripheral blood was collected from MBC patients with known PIK3CA mutation status serially prior to starting new standard therapies and on treatment. Cell-free DNA was extracted from plasma and sequenced using a custom capture panel (IDT). CTCs were isolated with VERSA microfluidic technology integrating capture with downstream analysis. CTCs were captured immunomagnetically followed by RNA isolation on chip and RNA-seq, or staining on chip for phospho-AKT pS473 and total AKT or phospho-rpS6 pS235/S236 and total rpS6, followed by quantification of single cell phospho/total protein mean fluorescence ratios. Results: In a pilot cohort of 14 patients, mean CTC phospho-AKT/total AKT protein expression ratio was higher in patients with PIK3CA mutations compared to patients without mutations (0.37 vs 0.26, p Conclusion: We have demonstrated the feasibility of a comprehensive liquid biopsy for simultaneous monitoring of PI3K pathway mutations in ctDNA and PI3K pathway signaling in CTCs via transcriptional profiling and phospho-protein expression in patients with MBC. Future work will prospectively evaluate this assay in patients receiving alpelisib for PIK3CA-mutated MBC. This has the potential to complement PIK3CA mutation status as a biomarker of sensitivity to PI3K therapies, and may also provide a pharmacodynamic assessment of PI3K inhibitor activity in CTCs on treatment. Citation Format: Marina N. Sharifi, Kyle T. Helzer, Jamie M. Sperger, Matthew L. Bootsma, Hannah Krause, Cole S. Gilsdorf, Serena K. Wolfe, Zachary Kauffman, Amye J. Tevaarwerk, Mark E. Burkard, Amanda M. Parkes, Ruth M. O'Regan, Kari B. Wisinski, Shuang G. Zhao, Joshua M. Lang. Simultaneous longitudinal assessment of PIK3CA genomic mutations and PI3K pathway activity in circulating tumor cells in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1955.

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor-positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor-positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

The Oncotype DX recurrence score (RS) is used as a tool for making decisions about chemotherapy for patients who have hormone receptor (estrogen receptor or progesterone receptor)-positive, HER2-negative breast cancer. There is no benefit from chemotherapy among patients aged ≥50 years who have lymph node-negative disease and an RS from 11 to 25, but the benefit of chemotherapy in the lymph node-positive group remains unknown.On the basis of data from the National Cancer Data Base between 2010 and 2014, a nationwide, retrospective cohort study included 73,185 women who had stage I through IIIA breast cancer and an RS between 11 and 30.Receipt of chemotherapy was associated with a reduced risk of death among patients who had lymph node-positive breast cancer (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.45-0.74; P.001) after adjusting for other prognostic factors in a multivariable Cox model. The 5-year survival gain ranged from 1.3% (RS 11-17 subgroup), to 3.3% (RS 18-25 subgroup), and to 6.7% (RS 26-30 subgroup). Among patients who had lymph node-negative disease, chemotherapy was associated with a reduced risk of death for those with an RS from 25 to 30 (HR, 0.68; 95% CI, 0.48-0.96; P = .03; 5-year survival gain, 1.8%), but there was no benefit from chemotherapy for patients who had an RS from 11 to 17 (HR, 0.97; 95% CI, 0.61-1.55; P = .90), and there was a marginally significant benefit for women who had an RS from 18 to 25 (HR, 0.79; 95% CI, 0.62-1.00; P = .05). Similar results were observed using propensity score-matching method.The benefit of chemotherapy for patients with breast cancer who have an intermediate RS is driven in a nonlinear fashion by RS: the higher the RS, the larger the absolute benefit. Findings from this study underscore the utility of real-world data to inform joint decision making in practice.

The use of hormonal therapy in breast cancer has improved the overall outcome for patients with early-stage hormone receptor-positive disease. The choice of hormone therapy is related to multiple factors, including menopausal state, patient preference, and potential side effects. Molecular profiling has allowed therapy to be tailored for an individual patient to some extent. However, further molecular studies are needed to individualize the choice and length of adjuvant hormone therapy. Ongoing studies are evaluating the role of additional targeted therapies, such as CDK4/6 inhibitors, to further improve outcome for patients with early-stage hormone receptor-positive breast cancer.

The use of gene expression profiling has impacted our understanding of breast cancer biology and increasingly has played a role in guiding clinical decisions. We have used hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status for years to guide selection of therapy. More recently, gene expression analysis has facilitated the identification of at least five intrinsic subtypes of breast cancer. Potential therapeutic targets have also been identified using genomic profiling. Several tests, such as the 21-gene recurrence score assay (Oncotype DX) and the 70-gene prognosis signature (MammaPrint), have been well validated as prognostic tools for early-stage breast cancer, and have aided in adjuvant therapy decisions for early-stage, HR-positive breast cancer patients. Genomic profiling has the potential to provide additional insight into drug discovery and clinical trial design by identifying appropriate targeted therapies for subtypes of breast cancer.

Tamoxifen (Fig. 1) is the endocrine treatment of choice for all stages of hormone-responsive breast cancer. Additionally tamoxifen has been shown to reduce the incidence of cancer of the opposite breast (1) and has recently been demonstrated to prevent breast cancer (2). Although most women with hormone-responsive advanced breast cancer respond to tamoxifen, their disease eventually becomes refractory to tamoxifen. These patients are known to respond to second-line hormonal therapies. In this chapter, we will focus on new antiestrogens that are currently available or are being developed for use following tamoxifen failure. We have divided these new agents into three groups according to their target-site specificity and molecular properties (3); tamoxifen-like agents, raloxifene-like agents, and pure antiestrogens.

Cross-resistance is an important issue for the evaluation of new antiestrogens to treat advanced breast cancer patients who have failed tamoxifen therapy. In addition, postmenopausal patients treated with long-term adjuvant tamoxifen show a 3-4-fold increase in the risk of developing endometrial cancer. Consequently, a new second line agent should be more antiestrogenic and less estrogen-like on the uterus, and be effective at controlling the growth of breast cancer after exposure to tamoxifen. The purpose was to evaluate the effects of the new tamoxifen analogue GW5638 on breast and endometrial cancer growth.Athymic mice were transplanted with an endometrial tumor model (ECC-1 E2) that is responsive to estrogen and has never been exposed to antiestrogen. In addition, we used three breast tumor models: a tamoxifen-naïve tumor (T47D-E2) and two tamoxifen-stimulated tumors (MT2 TAM and MCF-7 TAM LT). The antiestrogen GW5638 (1.5 mg daily), tamoxifen (0.5 mg or 1.5 mg daily), and raloxifene (1.5 mg daily) were given p.o. The pure antiestrogen ICI182,780 (5 mg once a week) was given s.c. Western blots from MCF-7 TAM breast tumors were performed to demonstrate the regulation of estrogen receptor alpha expression by different ligands.Estradiol and GW5638 down-regulated the receptor compared with control. ICI182,780 completely degraded the receptor but tamoxifen had no effect. GW5638 did not promote tumor growth, and was effective in blocking the effects of postmenopausal estradiol on the growth of tamoxifen-naïve breast and endometrial tumors. However, raloxifene did not completely block the effects of postmenopausal estradiol on the growth of tamoxifen-naïve endometrial tumor after 14 weeks. GW5638 and ICI182,780 but not raloxifene were also effective in blocking the tamoxifen-stimulated breast tumor growth in athymic mice.GW5638 is more effective than raloxifene in blocking the effect of estrogen on tamoxifen-naïve endometrial cancer. More importantly, GW5638, like the pure antiestrogen ICI182,780, is able to block the growth of breast cancer stimulated by tamoxifen differently from raloxifene. GW5638 down-regulates estrogen receptor but does not completely destroy the receptor. Therefore, based on our findings, GW5638 could be developed as a second line agent for advanced breast cancer patients and an important first line agent to evaluate as an adjuvant treatment or chemopreventive.

One in eight women in the United States will develop breast cancer. Family history, hormonal factors and benign breast disease have been identified as key factors in the development of breast cancer. Until recently the only treatment option for women identified as being at high risk of developing breast cancer was bilateral prophylactic mastectomy. Tamoxifen is the treatment of choice for patients with all stages of hormone-responsive breast cancer. Tamoxifen has a proven safety record from analysis of its use in patients with early stage breast cancer and, in postmenopausal women, it maintains bone density and lowers cholesterol levels. Lastly, tamoxifen reduces the incidence of contralateral breast cancer in women with breast cancer. Recently, in a large randomized trial where women at high risk of breast cancer were randomized to tamoxifen or placebo, tamoxifen resulted in a 50% reduction in the incidence of both invasive and non-invasive breast cancers. On the basis of this result, tamoxifen has been approved as a preventive for women at high risk of developing breast cancer. The optimum duration of tamoxifen in the preventive setting is to date unclear, but in the adjuvant setting, tamoxifen continues to have beneficial effects even after it is stopped. Tamoxifen does result in a two- to threefold increase in endometrial cancer, and new antiestrogens, such as raloxifene, are being developed to reduce this risk. The next prevention trial, called Study of Tamoxifen and Raloxifene (STAR), will randomize postmenopausal women to tamoxifen or raloxifene for five years.