Ductal carcinoma in situ and cause-specific mortality among younger and older postmenopausal women: the Women's Health Initiative.

BACKGROUND: Whether DCIS is associated with higher breast cancer-specific and all-cause mortality is unclear with few studies in older women. Therefore, we examined DCIS and breast cancer-specific, cardiovascular (CVD)-specific, and all-cause mortality among Women's Health Initiative (WHI) Clinical Trial participants overall and by age (< 70 versus ≥ 70 years). METHODS: Of 68,132 WHI participants, included were 781 postmenopausal women with incident DCIS and 781 matched controls. Serial screening mammography was mandated with high adherence. DCIS cases were confirmed by central medical record review. Adjusted multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Kaplan Meier (KM) plots were used to assess 10-year and 20-year mortality rates. RESULTS: After 20.3 years total, and 13.2 years median post-diagnosis follow-up, compared to controls, DCIS was associated with higher breast cancer-specific mortality (HR 3.29; CI = 1.32-8.22, P = 0.01). The absolute difference in 20-year breast cancer mortality was 1.2% without DCIS and 3.4% after DCIS, log-rank P = 0.026. Findings were similar by age (< 70 versus ≥ 70 years) with no interaction (P interaction = 0.80). Incident DCIS was not associated with CVD-specific mortality (HR 0.77; CI-0.54-1.09, P = 0.14) or with all-cause mortality (HR 0.96; CI = 0.80-1.16, P = 0.68) with similar findings by age. CONCLUSIONS: In postmenopausal women, incident DCIS was associated with over three-fold higher breast cancer-specific mortality, with similar findings in younger and older postmenopausal women. These finding suggest caution in using age to adjust DCIS clinical management or research strategies.

Bilateral Oophorectomy and Colorectal Cancer Incidence and Mortality in the Women's Health Initiative.

BACKGROUND: The few cohort studies examining oophorectomy and colorectal cancer risk provide mixed results. Therefore, we examined this issue in Women's Health Initiative Observational Study participants. METHODS: A total of 71,312 postmenopausal women were followed for 22.1 years (median). At enrollment, 55,643 (78%) had intact ovaries and 15,669 (22%) had undergone a bilateral oophorectomy. Colorectal cancers were verified by central medical record review with mortality findings enhanced by National Death Index queries. RESULTS: With 1,421 incident colorectal cancers, 450 colorectal cancer-specific mortalities, after controlling for covariates, bilateral oophorectomy was not associated with colorectal cancer incidence or colorectal cancer mortality. CONCLUSIONS: No significant associations between oophorectomy and colorectal cancer incidence and mortality were seen in a large cohort study with long follow-up. IMPACT: As the oophorectomy and colorectal cancer question remains open, further studies of high quality, even with null findings, should be encouraged.

Inflammation-related proteins as biomarkers of treatment-related behavioral symptoms: A longitudinal study of breast cancer patients and age-matched controls.

Background: Behavioral symptoms in breast cancer (BC) survivors have been attributed to cancer treatment and resulting inflammation. However, studies linking behavioral symptoms to BC treatment have observed patients only after some treatment. Our prospective study with pre-treatment baseline investigates post-treatment changes in inflammation-related biomarkers and whether those changes correlate with changes in symptoms. Methods: Participants were postmenopausal women, newly-diagnosed with stage 0-3 BC before any treatment (n = 173 "patients"), and age-matched women without cancer (n = 77 "controls"), who were assessed on plasma markers [soluble tumor necrosis factor receptor type 2 (sTNF-RII), interleukin (IL)-6, IL-1 receptor antagonist (IL-1RA), C-reactive protein (CRP)]) and symptoms (Physical Functioning, Pain, Attention/concentration, Perceived Cognitive Problems, Fatigue, Sleep Insufficiency, Depression). Participants were assessed again 1 month, 1 year, and 2 years after completing primary treatment or similar interval in controls. Generalized linear mixed models tested 4 treatments (surgery alone or with chemotherapy, radiation, or both) for association with change per marker. Joint models tested change per marker for association with change per symptom. Models considered demographic, socioeconomic, and clinical covariates. False Discovery Rate method controlled risk of error from multiple hypotheses. Results: At one month post-completion of treatment, sTNF-RII and IL-6 were elevated by all BC treatments, as were IL-1RA and CRP after surgery alone (all, p < 0.05). By 1 year, markers' average values returned to baseline. Throughout 2-year follow-up, increase-from-baseline in sTNF-RII, IL-1RA, and IL-6 coincided with worsened Physical Functioning, and increase-from-baseline in sTNF-RII coincided with increased Pain (all, p < 0.01). These biomarker-symptom associations (excepting IL-6) were exclusive to patients. No other symptoms worsened, and baseline Fatigue and Depression improved in all participants. Conclusions: BC treatment, even surgery, is associated with transient elevation in inflammatory markers. In patients post-treatment, increase-from-baseline in sTNF-RII accompanies increased Pain and decreased Physical Functioning, suggesting that sTNF-RII merits development as a clinical biomarker in BC patients.

Predicting All-Cause Mortality in Women With and Without Breast Cancer Using the Schonberg Index: A Women's Health Initiative Study.

BACKGROUND: When treating older women with breast cancer, life expectancy is an important consideration. ASCO recommends calculating 10-year mortality probabilities to inform treatment decisions. One useful tool is the Schonberg index, which predicts risk-based all-cause 10-year mortality. We investigated the use of this index in women aged ≥65 years with breast cancer in the Women's Health Initiative (WHI). METHODS: We calculated 10-year mortality risk scores for 2,549 WHI participants with breast cancer ("cases") and 2,549 age-matched breast cancer-free participants ("controls") using Schonberg index risk scoring. Risk scores were grouped into quintiles for comparisons. Risk-stratified observed mortality rates and 95% confidence intervals were compared across cases and controls. Observed 10-year mortality rates in cases and controls were also compared with Schonberg index-based predicted 10-year mortality rates. RESULTS: Compared with controls, cases were more often white (P=.005), had higher income and education levels (P<.001 for both), more often lived with their husband/partner (P<.001), scored higher on subjective health/happiness (P<.001), and needed less assistance in activities of daily living (P<.001). Participants with breast cancer had similar risk-stratified 10-year mortality rates compared with controls (34% vs 33%, respectively). Stratified results showed that cases had slightly higher mortality rates than controls in the lowest risk quintile and lower mortality rates in the 2 highest risk quintiles. Observed mortality rates in cases and controls were similar to Schonberg index-predicted mortality, with model c-indexes of 0.71 and 0.76, respectively. CONCLUSIONS: Among women aged ≥65 years with incident breast cancer, the Schonberg index-based risk-stratified 10-year mortality rates were similar to those in women without breast cancer, demonstrating a similar performance of the index among both populations. Along with other health measures, prognostic indexes can help predict survival among older women with breast cancer and support geriatric oncology guidelines that promote using life expectancy calculation tools for shared decision-making.

BRCA germline mutations in multiethnic gynecologic patients: A 10-year retrospective analysis from a single cancer institute.

Histologic and genetic mutation information from racially and ethnically diverse populations is warranted to better inform future cancer predisposition and promote health equity. A single institutional, retrospective capture of patients with gynecologic conditions and genetic susceptibilities to malignant neoplasms of the breast or ovaries was performed. This was achieved with manual curation of the electronic medical record (EMR) from 2010-2020 with the use of ICD-10 code searches. Among 8983 consecutive women identified with gynecologic conditions, 184 were diagnosed with pathogenic/likely pathogenic (P/LP) germline BRCA (gBRCA) mutations. Median age was 54 (22-90). Mutations included insertion/deletion (majority frameshift, 57.4%), substitution (32.4%), large structural rearrangement (5.4%), and alteration in splice site/intronic sequence (4.7%). A total of 48% were non-Hispanic White, 32% Hispanic or Latino, 13% Asian, 2% Black, and 5% Other. The most common pathology was high grade serous carcinoma (HGSC, 63%), followed by unclassified/high grade carcinoma (13%). Additional multigene panels led to the detection of 23 additional BRCA-positive patients with germline co-mutations and/or variants of uncertain significance in genes functionally involved in DNA repair mechanisms. Hispanic or Latino and Asian individuals comprised 45% of patients with concomitant gynecologic condition and gBRCA positivity in our cohort, confirming that germline mutations are represented across racial and ethnic groups. Insertion/deletion mutations, the majority of which led to a frameshift change, occurred in approximately half of our patient cohort, which may have prognostic implication for therapy resistance. Prospective studies are needed to unravel the significance of germline co-mutations in gynecologic patients.

Phase 2 prospective open label study of neoadjuvant nab-paclitaxel, trastuzumab, and pertuzumab in patients with HER2-positive primary breast cancer.

BACKGROUND: The objective of this study was to evaluate the safety and efficacy of nab-paclitaxel, trastuzumab, and pertuzumab as neoadjuvant therapy (NAT) in patients with human epidermal growth factor receptor 2 HER2+ breast cancer (HER2+ BC) to determine pathologic complete response (pCR), invasive disease-free survival (iDFS), and overall survival. METHODS: Forty-five patients with HER2+ BC Stages II-III were to be enrolled from 2013 to 2017. Patients were treated with weekly nab-paclitaxel (100 mg/m2 intravenously), weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg), and six cycles of pertuzumab (840 mg loading dose, then 420 mg intravenously day 1 every 21 days). RESULTS: Median follow-up was 60 months (95% CI, 32.3-55.6) and pCR was 29/45 (64%). The 5-year iDFS for patients who achieved pCR (N = 29) was 96.3% (95% CI, 76.5-99.5) and non-pCR patients (N = 16) was 74.3% (95% CI, 39.1-91.0). The 5-year overall survival (N = 45) was 94.1% (95% CI, 77.6-98.5). Based on hormonal status, the 5-year iDFS for HR+ pCR patients (N = 14) was 92.3% (95% CI, 56.6-98.9) and for HR- (N = 15) was 100% (p = .3). CONCLUSIONS: This anthracycline/carboplatin-free regimen with nab-paclitaxel achieved a pCR rate of 64% in patients with HER2+ BC. The 5-year iDFS in patients with and without pCR was 96.3% and 74.3%, respectively. The pCR rate is comparable with docetaxel, carboplatin, trastuzumab, and pertuzumab therapy in the NAT setting, but with fewer treatment-associated toxicities. This finding suggests the possibility of safe avoidance of anthracyclines and carboplatin as components of NAT in patients with HER2+ BC.

Emotional Distress and Financial Toxicity in Younger Adult Patients Undergoing Oncologic Surgery.

BACKGROUND: There has been an alarming increase in the number of young adults (YA) diagnosed with cancer. The emotional, psychosocial, and financial distress experienced by newly diagnosed YA undergoing cancer surgery remains largely unknown. METHODS: A validated biopsychosocial distress screening tool (SupportScreen) was administered to patients diagnosed with cancer before surgery between 2009 and 2017 in a National Cancer Institute Comprehensive Cancer Center. Patients were stratified into YA less than or equal to 45 years and older adults (OA) above 45 years. Descriptive statistics and logistic regression were used to analyze distress outcomes. RESULTS: In total, 4297 patients were identified, with YA comprising 13.3% (n=573) of the cohort. YA reported higher emotional distress, including increased anxiety (33.8% vs 27.4%, P =0.002), greater fear of procedures (26.7% vs 22%, P =0.018), and difficulty managing emotions (26% vs 20.7%, P =0.006). YA struggled more frequently to manage work/school (29.5% vs 19.3%, P <0.001), finding resources (17.8% vs 11.8%, P <0.001), changes in physical appearance (22.2% vs 13.4%, P <0.001), fatigue (36% vs 27.3%, P <0.001), and ability to have children (18.4% vs 3%, P <0.001). Financial toxicity was significantly higher in the YA group (40.5% vs 28%, P <0.001). While income level was strongly protective against emotional distress and financial toxicity in OAs, it was less protective against the risk of financial toxicity in YA. Younger age was an independent predictor of financial toxicity in a model adjusted to income (odds ratio=1.52, P =0.020). CONCLUSIONS: YA in the prime of their personal and professional years of productivity require special attention when undergoing surgical evaluation for cancer. Resource allocation and counseling interventions should be integrated as part of their routine care to expedite their return to optimal physical and holistic health and mitigate psychosocial distress and financial toxicity.

Cutaneous metastasectomy: Is there a role in breast cancer? A systematic review and overview of current treatment modalities.

Cutaneous metastases (CM) are neoplastic lesions involving the dermis or subcutaneous tissues, originating from another primary tumor. Breast cancer is commonest primary solid tumor, representing 24%-50% of CM patients. There is no "standard of care" on management. In particular, the role of surgery in the treatment of cutaneous metastases from breast carcinoma (CMBC) remains controversial. This systematic review evaluates the role of cutaneous metastasectomy in breast cancer and provides an overview of existing treatment types.

Tumor-infiltrating exhausted CD8+ T cells dictate reduced survival in premenopausal estrogen receptor-positive breast cancer.

CD8+ tumor-infiltrating lymphocytes (TILs) are associated with improved survival in triple-negative breast cancer (TNBC) yet have no association with survival in estrogen receptor-positive (ER+) BC. The basis for these contrasting findings remains elusive. We identified subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibited a distinct tumor microenvironment marked by amplified interferon-γ signaling-related pathways and higher programmed death ligand 1 expression. Paradoxically, higher levels of tumor-infiltrating CD8+ TEX associated with decreased overall survival of patients with ER+ BC but not patients with TNBC. Moreover, high tumor expression of a CD8+ TEX signature identified dramatically reduced survival in premenopausal, but not postmenopausal, patients with ER+ BC. Finally, we demonstrated the value of a tumor TEX signature score in identifying high-risk premenopausal ER+ BC patients among those with intermediate Oncotype DX Breast Recurrence Scores. Our data highlight the complex relationship between CD8+ TILs, interferon-γ signaling, and ER status in BC patient survival. This work identifies tumor-infiltrating CD8+ TEX as a key feature of reduced survival outcomes in premenopausal patients with early-stage ER+ BC.

A Cross-Sectional Study of Distress Levels in Patients with Newly Diagnosed Breast Cancer: The Impact of Race, Ethnicity, and Language Preference.

PURPOSE: Our objective was to assess distress levels in female breast cancer patients as a function of race, ethnicity, and preferred language. We hypothesized minority patients and non-English screen-takers would report higher distress levels compared to English screen-takers and non-Hispanic whites. METHODS: We conducted a retrospective observational study of female breast cancer patients at an NCI designated cancer center from 2009 to 2016 who were administered a validated biopsychosocial distress screening questionnaire. Self-reported data on race and ethnicity was collected. RESULTS: A total of 3,156 patients were included in the analysis; mean age of 56.3 (SD 12.25) years. The racial/ethnic cohort distribution included 54% non-Hispanic white (NHW), 19% Hispanic, 16% Asian, 7% Black/African American, and 4% other. On multivariable analysis only Hispanic patients were significantly more likely to report overall distress compared to NHW (OR [1.39; CI [1.03-1.87; p=0.03). Asians were significantly less likely to report distress in the functional domain (OR 0.71, CI [0.58-0.88]; p=0.002), while Black patients were significantly more likely to report highest distress levels in the physical (OR 1.53, CI [1.11-2.12]; p=0.01) domain. Hispanic Spanish screen-takers reported significantly more distress compared to Hispanic English screen-takers across all four domains of distress (p<0.05 for all). CONCLUSIONS: Top sources of distress in female breast cancer patients vary as a function of race, ethnicity, and preferred language. Future studies should focus on identifying effective, culturally appropriate targeted interventions to mitigate emotional distress levels in ethnic and racial minorities as well as non-English speaking patients with breast cancer.

Integrating Academic and Community Cancer Care and Research through Multidisciplinary Oncology Pathways for Value-Based Care: A Review and the City of Hope Experience.

As the US transitions from volume- to value-based cancer care, many cancer centers and community groups have joined to share resources to deliver measurable, high-quality cancer care and clinical research with the associated high patient satisfaction, provider satisfaction, and practice health at optimal costs that are the hallmarks of value-based care. Multidisciplinary oncology care pathways are essential components of value-based care and their payment metrics. Oncology pathways are evidence-based, standardized but personalizable care plans to guide cancer care. Pathways have been developed and studied for the major medical, surgical, radiation, and supportive oncology disciplines to support decision-making, streamline care, and optimize outcomes. Implementing multidisciplinary oncology pathways can facilitate comprehensive care plans for each cancer patient throughout their cancer journey and across large multisite delivery systems. Outcomes from the delivered pathway-based care can then be evaluated against individual and population benchmarks. The complexity of adoption, implementation, and assessment of multidisciplinary oncology pathways, however, presents many challenges. We review the development and components of value-based cancer care and detail City of Hope's (COH) academic and community-team-based approaches for implementing multidisciplinary pathways. We also describe supportive components with available results towards enterprise-wide value-based care delivery.

Phase II Trial of Neoadjuvant Carboplatin and Nab-Paclitaxel in Patients with Triple-Negative Breast Cancer.

BACKGROUND: In this phase II clinical trial, we evaluated the efficacy of the nonanthracycline combination of carboplatin and nab-paclitaxel in early stage triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Patients with newly diagnosed stage II-III TNBC (n = 69) were treated with neoadjuvant carboplatin (area under the curve 6) every 28 days for four cycles plus nab-paclitaxel (100 mg/m2 ) weekly for 16 weeks. Pathological complete response (pCR) and residual cancer burden (RCB) were analyzed with germline mutation status, tumor-infiltrating lymphocytes (TILs), TNBC molecular subtype, and GeparSixto immune signature (GSIS). RESULTS: Sixty-seven patients were evaluable for safety and response. Fifty-three (79%) patients experienced grade 3/4 adverse events, including grade 3 anemia (43%), neutropenia (39%), leukopenia (15%), thrombocytopenia (12%), fatigue (7%), peripheral neuropathy (7%), neutropenia (16%), and leukopenia (1%). Twenty-four patients (35%) had at least one dose delay, and 50 patients (72%) required dose reduction. Sixty-three (94%) patients completed scheduled treatment. The responses were as follows: 32 of 67 patients (48%) had pCR (RCB 0), 10 of 67 (15%) had RCB I, 19 of 67 (28%) had RCB II, 5 of 67 (7%) had RCB III, and 1 of 67 (2%) progressed and had no surgery. Univariate analysis showed that immune-hot GSIS and DNA repair defect (DRD) were associated with higher pCR with odds ratios of 4.62 (p = .005) and 4.76 (p = .03), respectively, and with RCB 0/I versus RCB II/III with odds ratio 4.80 (p = .01). Immune-hot GSIS was highly correlated with DRD status (p = .03), TIL level (p < .001), and TNBC molecular subtype (p < .001). After adjusting for age, race, stage, and grade, GSIS remained associated with higher pCR and RCB class 0/I versus II/III with odds ratios 7.19 (95% confidence interval [CI], 2.01-25.68; p = .002) and 8.95 (95% CI, 2.09-38.23; p = .003), respectively. CONCLUSION: The combination of carboplatin and nab-paclitaxel for early stage high-risk TNBC showed manageable toxicity and encouraging antitumor activity. Immune-hot GSIS is associated with higher pCR rate and RCB class 0/1. This study provides an additional rationale for using nonanthracycline platinum-based therapy for future neoadjuvant trials in early stage TNBCs. Clinical trial identification number: NCT01525966 IMPLICATIONS FOR PRACTICE: Platinum is an important neoadjuvant chemotherapy agent for treatment of early stage triple-negative breast cancer (TNBC). In this study, carboplatin and nab-paclitaxel were well tolerated and highly effective in TNBC, resulting in pathological complete response of 48%. In univariate and multivariate analyses adjusting for age, race, tumor stage and grade, "immune-hot" GeparSixto immune signature (GSIS) and DNA repair defect (DRD) were associated with higher pathological complete response (pCR) and residual cancer burden class 0/1. The association of immune-hot GSIS with higher pCR holds promise for de-escalating neoadjuvant chemotherapy for patients with early stage TNBC. Although GSIS is not routinely used in clinic, further development of this immune signature into a clinically applicable assay is indicated.

Use of HER2-Directed Therapy in Metastatic Breast Cancer and How Community Physicians Collaborate to Improve Care.

The development of new HER2-directed therapies has resulted in a significant prolongation of survival for women with metastatic HER2-positive breast cancer. Discoveries in the laboratory inform clinical trials which are the basis for improving the standard of care and are also the backbone for quality improvement. Clinical trials can be completed more rapidly by expanding trial enrollment to community sites. In this article we review some of the challenges in treating metastatic breast cancer with HER2-directed therapies and our strategies for incorporating our community partners into the research network.

Insurance Status Predicts Survival in Women with Breast Cancer: Results of Breast and Cervical Cancer Treatment Program in California.

BACKGROUND AND PURPOSE: The Breast and Cervical Cancer Treatment Program (BCCTP) Act, passed by Congress in 2000, provides time-limited coverage to uninsured breast or cervical cancer patients. We examine survival differences between BCCTP cases and insured controls. METHODS: Stage I-III breast cancer patients, covered under California's BCCTP from 2005 to 2009 (N = 6343), were 1:1 matched with California Cancer Registry controls on age, race/ethnicity, and cancer stage. Overall and disease-specific (OS and DSS) survival were compared using multivariate regression. RESULTS: BCCTP cases were more often unmarried [odds ratio (OR) 2.47, 95% confidence interval (CI) 2.30-2.66], with poorly/undifferentiated tumors (OR 1.26, CI 1.13-1.40), classified as ER negative (OR 1.10, CI 1.02-1.20) and/or PR negative (OR 1.09, CI 1.01-1.17). Cases were more likely to undergo mastectomy (OR 1.13, CI 1.05-1.21) or no surgery (OR 1.64, CI 1.31-2.05) versus lumpectomy. Cases were also more likely to undergo radiation (OR 1.11, CI 1.03-1.19). Endocrine therapy rates were marginally lower in cases (OR 0.93, CI 0.86-1.00). OS and DSS were shorter in BCCTP cases on multivariate analysis (HR 1.29, CI 1.17-1.42 and HR 1.27, CI 1.14-1.42, respectively). When stratified by socioeconomic status (SES), cases had significantly shorter OS and DSS except in the lowest quintile. When stratified by stage, cases had significantly shorter OS and DSS, except for stage I. CONCLUSIONS: The BCCTP provides uninsured breast cancer patients with comprehensive and timely care. Although our results suggest that BCCTP delivers quality care, BCCTP patients have shorter survival rates, even after accounting for SES and stage differences. Further assistance to vulnerable populations is warranted, including longer duration of treatment coverage, and surveillance adhering to NCCN compliant surveillance programs.

STAT3 Activation-Induced Fatty Acid Oxidation in CD8+ T Effector Cells Is Critical for Obesity-Promoted Breast Tumor Growth.

Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8+ T effector cells is critical for obesity-associated breast tumor progression. Ablating T cell Stat3 or treatment with an FAO inhibitor in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8+ T effector cell functions, leading to inhibition of breast tumor development. Moreover, PD-1 ligation in CD8+ T cells activates STAT3 to increase FAO, inhibiting CD8+ T effector cell glycolysis and functions. Finally, leptin enriched in mammary adipocytes and fat tissues downregulates CD8+ T cell effector functions through activating STAT3-FAO and inhibiting glycolysis. We identify a critical role of increased oxidation of fatty acids driven by leptin and PD-1 through STAT3 in inhibiting CD8+ T effector cell glycolysis and in promoting obesity-associated breast tumorigenesis.

Characterization of infections and hypogammaglobulinemia treated with the combination of pertuzumab and trastuzumab.

PURPOSE: We update a patient series that reported a high incidence of infection with Gram-positive cocci in women treated with the combination of pertuzumab and trastuzumab and further characterize this clinical problem. PATIENTS: Treating physicians and advanced practice partners identified women who developed infections while on treatment with pertuzumab and trastuzumab alone or in combination with chemotherapy and enrolled them onto this registry trial. RESULTS: Between March, 2014 and May, 2017, 48 patients with HER2-positive breast cancers were reported to have 59 individual infections. The median age was 48 years. Twenty-four patients received neoadjuvant therapy, 17 were treated for metastatic disease, and 7 were treated in the adjuvant setting. Pertuzumab and trastuzumab were combined with carboplatin and docetaxel in 24 (49%) patients, docetaxel in 10 (21%), nab-paclitaxel in 12 (24%), and without other agents in 2 (4%). Granulocyte growth factors were administered in 24 (49%) patients and no patients were documented to be neutropenic. Folliculitis developed in 25 (52%) patients and was counted as a single infection. Abscesses developed at a number of sites in 24 (49%) patients, including a septic knee requiring total knee replacement. Paronychia occurred in 7 (15%) patients, and 5 (10%) developed cellulitis. When cultures were obtained, Gram-positive cocci were consistently identified. Hypogammaglobulinemia was documented in 14 (36%) of the 33 patients tested. CONCLUSIONS: Our data continue to support an increased risk of infections with Gram-positive cocci as a potentially serious adverse event in women treated with pertuzumab and trastuzumab.

Resident memory CD8+ T cells within cancer islands mediate survival in breast cancer patients.

CD8+ tumor-infiltrating lymphocytes (TILs) correlate with relapse-free survival (RFS) in most cancer types, including breast cancer. However, subset composition, functional status, and spatial location of CD8+ TILs in relation to RFS in human breast tumors remain unclear. Spatial tissue analysis via quantitative immunofluorescence showed that infiltration of CD8+ T cells into cancer islands was more significantly associated with RFS than CD8+ T cell infiltration into either tumor stroma or total tumor. Localization into cancer islands within tumors is mediated by expression of the integrin CD103, which is a marker for tissue-resident memory T cells (TRMs). Analysis of fresh tumor samples revealed that CD8+ TRMs are functionally similar to other CD8+ TILs, suggesting that the basis of their protective effect is their spatial distribution rather than functional differences. Indeed, CD103+ TRMs, as compared with CD103-CD8+ TILs, are enriched within cancer islands, and CD8+ TRM proximity to cancer cells drives the association of CD8+ TIL densities with RFS. Together, these findings reveal the importance of cancer island-localized CD8+ TRMs in surveillance of the breast tumor microenvironment and as a critical determinant of RFS in patients with breast cancer.