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Supplementary Figure 1: Trial Enrollment Schema Supplementary Figure 2: Kaplan Meier Curve Among Patients Receiving Palbociclib and Paclitaxel

Supplemental Table 2: Pathologic complete response rates by route of vaccine administration and ER status in 42 DCIS patients

KM Curves

Supplemental Figure 1: CONSORT diagram of the 58 patients enrolled in the vaccine trial. A total of 54 were randomized to one of the three vaccination routes. After the twenty second patient completed the vaccine, subsequent ER positive patients were treated with concurrent anti-estrogen therapy.

Purpose:The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity (DLT) in patients with Rb protein–expressing, advanced breast cancer.Patients and Methods:This open-label, phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently between days 1 and 19 of a 28-day cycle alternating with weekly paclitaxel. Dose escalation proceeded in a standard 3 + 3 design. Ten additional patients received the combination at the recommended phase II dose (RP2D). Those who reached response plateau ≥6 cycles could continue on palbociclib alone on a 3 week on/1 week off schedule at one dose level above their combination dose.Results:Twenty-seven patients enrolled. Although there was only 1 DLT (grade 3 alanine aminotransferase/aspartate aminotransferase at 125 mg), neutropenia (NTP) requiring dose modification in cycle 1 (C1) resulted in an RP2D of 75 mg palbociclib/80 mg/m2 paclitaxel. During C1, the most common adverse event was NTP, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy were also observed in 8 patients each (29.6%). The clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes.Conclusions:Alternating sequential palbociclib/paclitaxel in patients with Rb+ advanced breast cancer is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb+ breast cancer regardless of subtype; efficacy trials are warranted.

Dose Cohort Scema

Supplemental Figure 4: The CD4pos Th1 immune response in the peripheral blood pre-vaccination and post-vaccination by clinical response (

Supplemental Table 1: Overall immune response detected in the peripheral blood by route of vaccine administration and ER status

Purpose: Vaccination with HER2 peptide-pulsed DC1s stimulates a HER2-specific T-cell response. This randomized trial aimed to establish safety and evaluate immune and clinical responses to vaccination via intralesional (IL), intranodal (IN), or both intralesional and intranodal (ILN) injection.Experimental Design: Fifty-four HER2pos patients [42 pure ductal carcinoma in situ (DCIS), 12 early invasive breast cancer (IBC)] were enrolled in a neoadjuvant HER2 peptide-pulsed DC1 vaccine trial. Patients were randomized to IL (n = 19), IN (n = 19), or ILN (n = 16) injection. Immune responses were measured in peripheral blood and sentinel lymph nodes by ELISPOT or in vitro sensitization assay. Pathologic response was assessed in resected surgical specimens.Results: Vaccination by all injection routes was well tolerated. There was no significant difference in immune response rates by vaccination route (IL 84.2% vs. IN 89.5% vs. ILN 66.7%; P = 0.30). The pathologic complete response (pCR) rate was higher in DCIS patients compared with IBC patients (28.6% vs. 8.3%). DCIS patients who achieved pCR (n = 12) and who did not achieve pCR (n = 30) had similar peripheral blood anti-HER2 immune responses. All patients who achieved pCR had an anti-HER2 CD4 immune response in the sentinel lymph node, and the quantified response was higher by response repertoire (P = 0.03) and cumulative response (P = 0.04).Conclusions: Anti-HER2 DC1 vaccination is a safe and immunogenic treatment to induce tumor-specific T-cell responses in HER2pos patients; immune and clinical responses were similar independent of vaccination route. The immune response in the sentinel lymph nodes, rather than in the peripheral blood, may serve as an endpoint more reflective of antitumor activity. Clin Cancer Res; 23(12); 2961–71. ©2016 AACR.

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Supplementary Table 3 from Telomerase-Specific T-Cell Immunity in Breast Cancer: Effect of Vaccination on Tumor Immunosurveillance

Supplementary Table 2 from Telomerase-Specific T-Cell Immunity in Breast Cancer: Effect of Vaccination on Tumor Immunosurveillance

Supplementary Figure 5 from Targeting HER-2/neu in Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion

Supplementary Figure 4 from Targeting HER-2/neu in Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion

The human telomerase reverse transcriptase (hTERT) is nearly universally overexpressed in human cancer, contributes critically to oncogenesis, and is recognized by cytotoxic T cells that lyse tumors. CD8+ T cells specific for hTERT naturally occur in certain populations of cancer patients in remission, but it remains poorly understood whether such T cells could contribute to tumor immunosurveillance. To address this issue, we induced hTERT-specific T cells in vivo via peptide vaccination in 19 patients with metastatic breast cancer who otherwise had no measurable T-cell responses to hTERT at baseline. Tumor-infiltrating lymphocytes (TIL) were evident after, but not before vaccination, with 4% to 13% of postvaccine CD8+ TIL specific for the immunizing hTERT peptide. Induction of TIL manifested clinically with tumor site pain and pruritus and pathologically with alterations in the tumor microenvironment, featuring histiocytic accumulation and widespread tumor necrosis. hTERT-specific CD8+ T cells were also evident after vaccination in the peripheral blood of patients and exhibited effector functions in vitro including proliferation, IFN-γ production, and tumor lysis. An exploratory landmark analysis revealed that median overall survival was significantly longer in those patients who achieved an immune response to hTERT peptide compared with patients who did not. Immune response to a control cytomegalovirus peptide in the vaccine did not correlate with survival. These results suggest that hTERT-specific T cells could contribute to the immunosurveillance of breast cancer and suggest novel opportunities for both therapeutic and prophylactic vaccine strategies for cancer. [Cancer Res 2007;67(21):1–9]

Supplementary Table 1 from Telomerase-Specific T-Cell Immunity in Breast Cancer: Effect of Vaccination on Tumor Immunosurveillance

Supplementary Table 1 from Targeting HER-2/neu in Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion

Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neupos DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-γ and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu–HLA-A2 tetramer-staining CD8pos T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-γ–secreting CD4pos (85%) and CD8pos (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of “immunoediting” for HER-2/neu–expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer. [Cancer Res 2007;67(4):1842–52]

Supplementary Figure 2 from Targeting HER-2/neu in Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion

Background: Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor outcomes and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) metastatic breast cancer (MBC). We previously presented clinical outcomes of JAKEE, a single arm, phase II, Simon two-stage clinical trial that tested Ruxolitinib (Rux), an oral selective inhibitor of JAK1/2, and exemestane (EXE) in 25 participants (pts) with HR+ MBC that relapsed/progressed on non-steroidal AI (NSAI); specifically, the primary endpoint of safety was met, but there were no complete or partial responses and 6/25 (24%) achieved stable disease (SD) for ≥6 cycles. We investigated whether host circulating inflammatory markers, IL-6 genotypes, and estrogen levels were associated with differential response to therapy.Methods: Responders (R) were defined as having achieved SD≥6 cycles. Flow cytometry was performed on baseline and on-treatment peripheral blood samples to assess downstream CD3+ T-cell phosphoSTAT3 inhibition by Rux. Serum concentrations of C-reactive protein (CRP), IL-6, serum amyloid A (SAA), Estrone (E1) and Estradiol (E2) were measured at baseline and serially on treatment. Sanger sequencing was performed to assess for three functional variants of the IL-6 promoter: −572G>C (rs1800796), −597G>A (rs1800797), and −174G>C (rs1800795), with high-risk polymorphisms being -597G/G and/or -174G/G. Non-parametric median testing was employed to test for differences in circulating markers by response groups given non-normal distribution, with a two-sided alpha of 0.05.Results: The cohort was heavily pre-treated: 28% received ≥2 lines of chemotherapy for MBC and 20% had CNS disease at enrollment. Among 17/25 pts with samples for pharmacodynamic assessment, Rux exhibited a 25% median inhibition (range 0-77%) of phosphoSTAT3. There was no differential effect in R vs non-responders (NR) (median inhibition 20% vs 29%, p=0.15). Frequency of high-risk IL-6 genotypes and distribution of baseline serum CRP, IL-6, SAA, E1 and E2 are depicted in the table. 15/25 (60%) harbored a high-risk IL-6 promoter polymorphism, with no significant difference in frequency between R and NR (50% vs 63%, p=0.65). 19 pts had samples for inflammatory biomarker analysis. 16/19 had baseline CRP≥10mg/L. While median levels of baseline CRP, SAA, and IL-6 were above upper limit of normal, there was no difference between R and NR (table). The proportion of pts with baseline undetectable E1 and E2 were similar between R and NR (E1: 36.9% vs 33.3%, p=1.0, E2: 52.6% vs 50%, p=1.0); notably, a significantly lower proportion with high-risk IL-6 genotype had undetectable baseline E1 (20% vs 60%, p=0.041), while no difference was noted for baseline E2, nor in the % change in E1 or E2 levels from baseline to cycle 4 by responder status.Conclusions: The JAKEE cohort represents an inflamed population with elevated circulating inflammatory markers and a high proportion with high-risk IL-6 genotypes. Examination of host inflammatory markers, IL-6 genotypes and estrogen levels did not reveal a differential response to the combination of Rux and EXE in patients with HR+ MBC that had progressed on prior NSAI. At tolerable dosing, Rux exhibited only a modest inhibition of phosphoSTAT3. Further work is needed to optimize strategies for targeting inflammation and JAK/STAT signaling in HR+ MBC. IL-6 GenotypeFrequencyFrequency by ResponderSignificanceHigh-Risk -174G/G and/or -597G/G15/25 (60%)Non-responder12/19 (63.2%)Responder3/6 (50%)p-value0.56Pretreatment Inflammatory Biomarkers [Upper limit of normal]Median (Range)Median Level by Responder GroupSignificanceCRP [8mg/L]SAA [10mg/L]IL-6 [2pg/mL]24.0 (0.2-146.8)12.8 (2.8-162.5)4.2 (1.8-11.5)Non-responder23.219.84.5Responder24.7 12.42.7p-value0.510.150.15Baseline Estrogen BiomarkersMedian (Range)Non-responderResponderp-valueEstrone (E1) (pg/mL)Estradiol (E2) (pg/mL)79.5.0 (0.2-1039.0)0.2 (0.2-44.1)79.8 0.247.8 4.20.410.91 Citation Format: Igor Makhlin, Nicholas McAndrew, E. Paul Wileyto, Amy Clark, Robin Holmes, Lisa N Bottalico, Grace R Jeschke, Kevin R Fox, Susan M Domcheck, Jennifer M Matro, Angela R Bradbury, Natalie Shih, Michael D Feldman, Elizabeth O Hexner, Jacqueline F Bromberg, Angela DeMichele. Analysis of host inflammatory and estrogen biomarkers in JAKEE: A phase II trial of the JAK inhibitor ruxolitinib in combination with exemestane for estrogen receptor-positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-04.

Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4–45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6–3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.

Objective: This article reports on the development, implementation, and evaluation of an integrative clinical oncology massage program for patients undergoing chemotherapy for breast cancer in a large academic medical center. Materials and Methods: We describe the development and implementation of an oncology massage program embedded into chemoinfusion suites. We used deidentified program evaluation data to identify specific reasons individuals refuse massage and to evaluate the immediate impact of massage treatments on patient-reported outcomes using a modified version of the Distress Thermometer delivered via iPad. We analyzed premassage and postmassage data from the Distress Thermometer using paired t test and derived qualitative data from participants who provided written feedback on their massage experiences. Results: Of the 1,090 massages offered, 692 (63%) were accepted. We observed a significant decrease in self-reported anxiety (from 3.9 to 1.7), nausea (from 2.5 to 1.2), pain (from 3.3 to 1.9), and fatigue (from 4.8 to 3.0) premassage and postmassage, respectively (all P < .001). We found that 642 survey participants (93%) were satisfied with their massage, and 649 (94%) would recommend it to another patient undergoing treatment. Spontaneous patient responses overwhelmingly endorsed the massage as relaxing. No adverse events were reported. Among the 398 patients (36%) who declined a massage, top reasons were time concerns and lack of interest. Conclusion: A clinical oncology massage program can be safely and effectively integrated into chemoinfusion units to provide symptom control for patients with breast cancer. This integrative approach overcomes patient-level barriers of cost, time, and travel, and addresses the institutional-level barrier of space.

A recent study reported that time to adjuvant chemotherapy (TTC) 30 days was significantly associated with worse OS and DFS in triple-negative breast cancer (TNBC). Earlier studies, however, found that worse outcomes were associated with TTC 60 days or 90 days. As the trend for mastectomy with reconstruction continues to rise, TTC of 30 days is often not feasible due to wound-healing issues in some of these patients. To elucidate the impact of TTC, we sought to evaluate the clinical outcomes associated with TTC in a contemporary cohort treated for TNBC at a single institution.A single-institution database was queried to identify nonmetastatic TNBC patients who received adjuvant chemotherapy from 2009 to 2018. TTC was defined as interval between date of surgery and adjuvant chemotherapy start date. Median TTC was used to divide our cohort into four quartiles; ≤ 31, 32-42, 43-56, and 56 days. Logrank, Kaplan-Meier, and inverse probability weighting (IPW) tests were used to analyze disease-free (DFS) and overall survival (OS).The mean TTC of our study cohort (n = 724) was 48 days (median TTC = 42 days). Black race, mastectomy without adjuvant radiation, and mastectomy with immediate reconstruction were associated with delayed TTC (all p-values 0.01). In multivariate IPW analysis, TTC 56 (n = 173) days did not impact DFS or OS compared to TTC ≤ 31 (n = 198) days (p = 0.27 and p = 0.21, respectively). Similar results were seen during subgroup analysis for groups identified as higher risk for delayed TTC.Our results demonstrated that TTC was not significant or significantly associated with DFS or OS in patient receiving chemotherapy for operable TNBC. Our results were reassuring for patients electing mastectomy with immediate reconstruction, who may experience a longer TTC.

PURPOSE OF REVIEW To outline the risks of infertility from breast cancer treatment, and to illustrate current techniques in preserving fertility in breast-cancer patients who wish to become pregnant after treatment is concluded. RECENT FINDINGS Breast cancer often affects women of reproductive age. Although treatment is effective, cytotoxic chemotherapy causes ovarian reserve depletion, whereas hormonal therapy necessitates a delay in pregnancy, resulting in infertility. Patients of reproductive age should be referred to fertility specialists to explore methods of fertility preservation upon diagnosis. The best established method of fertility preservation is embryo cryopreservation, although investigational techniques such as, oocyte and ovarian tissue cryopreservation, may hold potential. Embryo cryopreservation involves ovarian stimulation to retrieve oocytes in-vitro fertilization prior to freezing. Techniques for the cryopreservation of unfertilized oocytes are under investigation. Successful pregnancies have resulted in breast cancer patients after treatment, without obvious compromise in their risk of recurrence or death from breast cancer. SUMMARY Ovarian stimulation with retrieval of ooctyes for in-vitro fertilization remains the best known option for fertility preservation in women with early stage breast cancer whose risk of fertility may be compromised by adjuvant chemotherapy.

BACKGROUND Skin-sparing mastectomy (SSM) followed by immediate reconstruction is an effective treatment option for patients with early-stage breast carcinoma, but its use in patients with more advanced disease is controversial. METHODS A retrospective review was performed that included 38 consecutive patients with high-risk breast carcinoma who underwent SSM and immediate reconstruction (between July 1996 and January 2002). Tumor characteristics, type of reconstruction, margin status, timing of adjuvant therapy, postoperative complications, and incidence of recurrence were evaluated. RESULTS High-risk patients (Stage IIA [n = 4 patients] Stage IIB [n = 23 patients] Stage IIIA [n = 8 patients] and Stage IIIB [n = 3 patients]) underwent immediate reconstruction after SSM with the use of a transverse rectus abdominis myocutaneous flap (n = 31 patients), a latissimus dorsi myocutaneous flap plus an implant (n = 3 patients), or tissue expanders with subsequent implant placement (n = 4 patients). The median follow-up was 52.9 months (range, 27.5–92.0 months), and the median time to recurrence has not yet been reached at the time of last follow-up. The median interval from surgery to the initiation of postoperative adjuvant therapy was 38 days (range, 25–238 days). Local recurrence was seen in 1 patient (2.6%), systemic recurrence in was seen in 10 patients (26.3%), and both local and distant metastases in were seen in 2 other patients (5.3%). CONCLUSIONS SSM with immediate reconstruction appeared to be an oncologically safe treatment option for high-risk patients with advanced stages of breast carcinoma. In addition to the aesthetic and psychological benefits of performing SSM with immediate reconstruction, local recurrence rates and disease-free survival were favorable when combined with the use of radiation therapy and adjuvant chemotherapy, as indicated. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND Advances in the diagnosis and treatment of breast carcinoma have led to a multidisciplinary approach to management for patients with breast carcinoma. To assess the effect of this approach, the authors performed an evaluation for a cohort of patients examined in a multidisciplinary breast cancer center. METHODS An analysis was performed for the records of 75 consecutive women with 77 breast lesions examined in consultation in a multidisciplinary breast cancer center between January and June 1998. Each patient's case was evaluated by a panel consisting of a medical oncologist, surgical oncologist, radiation oncologist, pathologist, diagnostic radiologist, and, when indicated, plastic surgeon. A comprehensive history and physical examination was performed, and the relevant mammograms, pathology slides, and medical records were reviewed. Treatment recommendations made before this evaluation were compared with the consensus recommendations made by the panel. RESULTS For the 75 patients, the multidisciplinary panel disagreed with the treatment recommendations from the outside physicians in 32 cases (43%), and agreed in 41 cases (55%). Two patients (3%) had no treatment recommendation before consultation. For the 32 patients with a disagreement, the treatment recommendations were breast-conservation treatment instead of mastectomy (n = 13; 41%) or reexcision (n = 2; 6%); further workup instead of immediate definitive treatment (n = 10; 31%); treatment based on major change in diagnosis on pathology review (n = 3; 9%); addition of postmastectomy radiation treatment (n = 3; 9%); or addition of hormonal therapy (n = 1; 3%). CONCLUSIONS The multidisciplinary breast cancer evaluation program provided an integrated program in which individual patients were evaluated by a team of physicians and led to a change in treatment recommendation for 43% (32 of 75) of the patients examined. This multidisciplinary program provided important second opinions for many patients with breast carcinoma. Cancer 2001;91:1231–7. © 2001 American Cancer Society.