Secondary Breast Cancer Research Articles

Impact of Germline <i>BRCA</i> Mutation Status on Survival in Women with Metastatic Triple Negative Breast Cancer

Purpose: To investigate the association between germline deleterious <i>BRCA1</i> or BRCA2</i> mutations (g<i>BRCA+</i>) and overall survival (OS) for patients with metastatic triple negative breast cancer (mTNBC). Methods: An IRB approved prospective multisite registry enrolling stage I-IV TNBC patients from 2011-2018 was utilized. Demographics, treatments, genetic results, recurrence and survival were collected. OS was estimated according to the Kaplan-Meier method and compared between groups (g<i>BRCA</i>+and <i>BRCA</i> wild type, wt) by log-rank test. Cox regression model was used for univariate and multivariate analysis of factors associated with risk of death. Results: 100 patients with mTNBC were enrolled on the registry between 2011- 2018. For 100 patients, 20% (20/100) had <i>de novo</i> stage IV whereas 80% (80/100) had metastatic recurrence. 12% had g<i>BRCA</i>+ status; 72% were g<i>BRCA</i> wt type; and 16% had unknown g<i>BRCA</i> status. g<i>BRCA</i>+ patients were younger (49 vs. 57 years, p</i>=0.02) but otherwise well matched to g<i>BRCA</i> wt including similar metastatic disease burden and prior treatments. No patients received a PARP inhibitor. With 31 months median follow-up, median overall survival was 21 months (95% CI [13-23] months) for all patients, 18 months (95% CI [15-27] months) for g<i>BRCA</i> wt patients and has not yet been reached for gBRCA</i>+ patients (<i>p</i>=0.023). 3-year estimated OS is 63% in g<i>BRCA</i>+ versus 28% in g<i>BRCA</i> wt (<i>p</i>=0.02). On multivariate analysis, g<i>BRCA</i>+ was associated with reduced risk of death (HR=0.33; 95%CI [0.23-0.91], <i>p</i>=0.033). Conclusions: In patients with mTNBC g<i>BRCA</i>+ patients have a clinically significantly improved 3-year OS compared to gBRCA</i> wt patients. Further research is needed to understand tumor and host biological reasons for this observation. As these patients are at risk for primary site progression and secondary breast and ovarian cancers, further research regarding the role of proactive surgical treatment in mTNBC with g<i>BRCA</i> mutation is warranted.

Patient-Reported Survivorship Care Practices and Late Effects After Treatment of Hodgkin and Non-Hodgkin Lymphoma.

Multimodal treatment of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) yields excellent outcomes; however, survivors are at risk of developing myriad late and long-term effects. From a convenience sample of 964 survivors of HL (37%) and NHL (63%) using a publicly available Internet-based survivorship care plan (SCP) tool between 2011 and 2016, we examined patient-reported cancer care, toxicities, and survivorship care data. Of all survivors, 67% were female and 84% were white and 88% were free of cancer. Median age of diagnosis was 28 years for survivors of HL and 49 years for NHL. Many survivors reported treatment with chemotherapy (92%), surgery (52%), and/or radiation (41%), with most radiation delivered to chest/mantle fields (81%). Survivors reported a diversity of radiation- and chemotherapy-related sequelae, including thyroid dysfunction, speaking and/or swallowing changes, pulmonary fibrosis/pneumonitis, heart disease, chronic fatigue, neurocognitive decline, neuropathy, sexual changes, and secondary breast cancers. Few reported receipt of previous survivorship information. Most reported management/comanagement by an oncology specialist after active treatment; however, a shift to management by primary care provider alone was observed as a trend over time in follow-up. Sixty-six percent of users who responded to a follow-up survey reported that they intend to share the SCP with their health care team. Survivors of lymphoma, many of whom are free of disease, report a substantial burden of late and long-term adverse effects, suboptimal delivery of survivorship information, and transitions of care in follow-up in which fragmented systems and/or poor communication may contribute to unmet survivor needs. Multiple opportunities thus exist for which SCPs may be used to improve awareness regarding survivorship and associated adverse effects in addition to communicating follow-up care plans between survivors and treatment teams.

Secondary Breast Cancer after DCIS: Impact of Initial Radiation Therapy on Mortality Associated with Invasive Second Breast Cancers

Secondary Breast Cancer after DCIS: Impact of Initial Radiation Therapy on Mortality Associated with Invasive Second Breast Cancers

Individualized estimates of overall survival in radiation therapy plan optimization - A concept study.

Current radiation therapy planning uses a set of defined dose-volume constraints to ensure a specified level of tumor coverage while constraining the dose distribution in the organs at risk. Such constraints are aggregated, population-based quantities that do not adequately consider patient-specific risk factors. Furthermore, these constraints are calculated for each organ independently and it is therefore not guaranteed that the optimal trade-off between organs is achieved. We introduce a novel radiotherapy planning approach where a patient-specific all-cause mortality risk is minimized using inverse plan optimization. As illustration of concept, our outcome risk model incorporates patient age, sex, cardiac risk factor (CRF), and smoking. We retrospectively analyzed a left-sided breast cancer case and a Hodgkin's lymphoma case, both clinically treated with three-dimensional conformal radiotherapy (3D-CRT). Our objective function for inverse plan optimization was an equally weighted summation of risk models for cancer recurrence and mortality from radiation-induced coronary heart disease and secondary lung and breast cancers incorporating patient age, sex, CRF, and smoking. We allowed the optimization algorithm to choose from a large set of gantry angles. The optimization task was to choose beams and optimize monitor units (MUs) so that overall survival was maximized (and the total risk of cancer recurrence and mortality from radiation-induced causes were minimized). The sensitivity analysis was performed in the lymphoma case by changing the tumor control probability model from using mean dose (Model 1) to using generalized equivalent uniform dose (Model 2). For the breast case in this study, the 3D-CRT clinical plan used eight beams while the proposed 3D-CRT outcome-optimized plan used five beams, reducing the total risk - summation of the risks of recurrence and secondary disease mortality - from 3% to 2%. The mean doses to clinical target volume (CTV) and internal mammary nodes (IMN) were increased in the outcome-optimized plan by 1.9 and 1.8Gy, respectively. For the Hodgkin's lymphoma case, the clinical 3D-CRT plan used two beams, while the proposed 3D-CRT outcome-optimized plan used three beams, reducing the total risk by 6% (from 16% to 10%). Using either of the two tumor control models for the lymphoma case resulted in outcome-optimized plans where tumor control was compensated at the cost of saving organs at risk. However, the impact of sensitivity to models was comparatively large. Using Model 1 resulted in a reduction in mean target dose by 15.2 vs 7.1Gy for Model 2. In all cases, the chosen beams in outcome-optimized plans were different from clinically used beams. The proposed optimization strategy, supplanting dosimetric objectives with comprehensive individual risk estimates, has the potential to yield improved outcomes in terms of reduced mortality risk in cancer patients treated with radiotherapy. The approach is, however, currently limited by gaps in knowledge about the effect of compromising dose to part of the target, for example, in order to spare cardiac structures.

Secondary Breast, Ovarian, and Uterine Cancers After Colorectal Cancer: A Nationwide Population-Based Cohort Study in Korea.

The risk of a second primary cancer has increased along with the increasing life expectancies of colorectal cancer survivors. We aimed to evaluate the incidence rate and risk factors of breast and gynecological (ovarian, uterine cervix/corpus) cancers among female colorectal cancer survivors. This is a retrospective population-based cohort study. This study used data from the National Health Insurance Corporation of Korea. Each patient with colorectal cancer diagnosed from 2007 to 2012 was followed until 2015 and compared with age-matched women without colorectal cancer at a 1:5 ratio. The primary outcome was de novo breast/gynecological cancer. Patients with available medical checkup data were included in an additional analysis. We analyzed 56,682 patients with colorectal cancer and 288,119 age-matched noncolorectal cancer controls. The risk of breast/gynecological cancer was higher among patients with colorectal cancer than among controls (HR, 2.91; p < 0.001). The association with colorectal cancer was the highest for ovarian cancer (HR, 6.72), followed by uterine corpus cancer (HR, 3.99), cervical cancer (HR, 2.82), and breast cancer (HR, 1.85). This association remained consistent in the subgroup analysis of medical checkup data (14,190 patients with colorectal cancer, 71,933 controls). Among patients with colorectal cancer, those aged <55 years had a higher risk of breast/gynecological cancers than those aged >55 years (HR, 3.51 vs 2.59), and those with dyslipidemia had a higher risk of breast cancer than those without dyslipidemia (HR, 2.66 vs 2.06). This was a retrospective, population-based study. A prospectively designed study is needed to validate our conclusions. Compared with the general population, patients with colorectal cancer carry a higher risk of developing secondary breast, ovarian, and uterine cancers. See Video Abstract at http://links.lww.com/DCR/A731.

CN40 - Developing a patient reported experience measure (PREM) in secondary breast cancer (SBC)

CN40 - Developing a patient reported experience measure (PREM) in secondary breast cancer (SBC)

Comparison of butterfly volumetric modulated arc therapy to full arc with or without deep inspiration breath hold for the treatment of mediastinal lymphoma

PurposeRadiotherapy is an effective treatment for mediastinal lymphoma but induces late effects including cardiac toxicity and secondary breast and lung cancer. Therefore reducing the dose to these organs is vital. We compared full arc volumetric modulated arc therapy (F-VMAT) against limited angle ‘Butterfly’ VMAT (B-VMAT) on free breathing (FB) and deep inspiration breath-hold (DIBH) computed tomography scans. The aim was to assess the benefits of B-VMAT over F-VMAT and to establish if the addition of DIBH results is a cumulative benefit. Materials and methodsF-VMAT and B-VMAT plans were calculated for 20 consecutive patients (15 females) with mediastinal lymphoma on both FB and DIBH scans. The planning target volume V95% was kept comparable between all plans while reducing organ doses as much as possible. ResultsB-VMAT significantly reduced low lung doses (V5–10), while F-VMAT was better for higher lung doses (V20–30). DIBH further improved lung doses for both types of plans. DIBH B-VMAT produced the lowest mean lung dose. With FB, heart doses were slightly higher for B-VMAT but the maximum difference was small (0.8% for V20) and only statistically significant for V10-20. The mean heart dose increased by only 0.1 Gy. The addition of DIBH however significantly reduced heart doses. While DIBH F-VMAT had the lowest heart doses, the difference was small compared with DIBH B-VMAT. B-VMAT significantly reduced breast V4 while DIBH reduced the V10. ConclusionB-VMAT and DIBH are both effective in reducing organ doses and the dosimetric benefit is additive for some parameters and complementary for others.

Breast Cancer, Secondary Breast Cancers in Childhood Cancer Male Survivors—Characteristics and Risks

Male breast cancer (MBC) is uncommon, accounting for less than 1% of all breast cancers. Secondary breast cancers among childhood cancer survivors have been well described in the literature, but less is known about MBC. We carried out an analysis in a cohort of 7019 five-year survivors of a solid childhood (aged ≤20years) cancer treated in France before 2001 and followed for an average of 20years and compared breast cancers occurring in both men and women. Among the 7019 survivors, 4 out of 3893 male survivors developed breast cancer, compared with 99 out of 3126 female survivors. All of the men had a history of radiation therapy. The 4 men with MBC had estrogen receptors and 3 had progesterone receptors. MBC is a rare second malignancy among childhood cancer survivors. Receipt of radiation therapy is a recognized risk factor, but more data about eventual genetic mutations are necessary. Regular screening based only on a history of radiation therapy is not recommended; however, attention must be given in the case of suspicious symptoms.

BRCA mutation in breast cancer patients: Prognostic impact and implications on clinical management.

BRCA1/2 mutations are involved in breast cancer (BC) susceptibility but their influence on outcome is unclear. We reviewed BC patients tested for BRCA to determine biological features and influence on outcome. BRCA-1 was correlated to younger age (P=0.035), nodal involvement (P=0.030), higher tumor grade (P=0.0022) and Ki-67 (P=0.014), ER/PgR negative status (P=0.00042 and 0.0091, respectively), and use of adjuvant chemotherapy (P=0.000038); BRCA was neither predictive for chemotherapy administration nor resulted in impaired outcome or occurrence of secondary BC. BRCA status did not influence outcome despite higher biological aggressiveness and younger age at presentation.

Stromal PTEN determines mammary epithelial response to radiotherapy

The importance of the tumor–associated stroma in cancer progression is clear. However, it remains uncertain whether early events in the stroma are capable of initiating breast tumorigenesis. Here, we show that in the mammary glands of non-tumor bearing mice, stromal-specific phosphatase and tensin homolog (Pten) deletion invokes radiation-induced genomic instability in neighboring epithelium. In these animals, a single dose of whole-body radiation causes focal mammary lobuloalveolar hyperplasia through paracrine epidermal growth factor receptor (EGFR) activation, and EGFR inhibition abrogates these cellular changes. By analyzing human tissue, we discover that stromal PTEN is lost in a subset of normal breast samples obtained from reduction mammoplasty, and is predictive of recurrence in breast cancer patients. Combined, these data indicate that diagnostic or therapeutic chest radiation may predispose patients with decreased stromal PTEN expression to secondary breast cancer, and that prophylactic EGFR inhibition may reduce this risk.

Caring for people with secondary breast cancer

Caring for people with secondary breast cancer

High resolution volumetric imaging of primary and secondary tumor spheroids using multi-angle Light Sheet Fluorescence Microscopy (LSFM).

Breast cancer and Glioblastoma brain cancer are severe malignancies with poor prognosis. In this study, primary Glioblastoma and secondary breast cancer spheroids are formed and treated with the well-known Temozolomide and Doxorubicin chemotherapeutics, respectively. High resolution imaging of both primary and secondary cancer cell spheroids is possible using a custom multi-angle Light Sheet Fluorescence Microscope. Such a technique is successful in realizing preclinical drug screening, while enables the discrimination among physiologic tumor parameters.

Epigenomic and Transcriptomic Characterization of Secondary Breast Cancers.

Molecular alterations impact tumor prognosis and response to treatment. This study was designed to identify transcriptomic and epigenomic signatures of breast cancer (BC) tumors from patients with any prior malignancy. RNA-sequencing and genome-wide DNA methylation profiles from BCs were generated in the Cancer Genome Atlas project. Patients with secondary breast cancer (SBC) were separated by histological subtype and matched to primary breast cancer controls to create two independent cohorts of invasive ductal (IDC, n = 36) and invasive lobular (ILC, n = 40) carcinoma. Differentially expressed genes, as well as differentially methylated genomic regions, were integrated to identify epigenetically regulated abnormal gene pathways in SBCs. Differentially expressed genes were identified in IDC SBCs (n = 727) and in ILC SBCs (n = 261; Wilcoxon's test; P < 0.05). In IDC SBCs, 105 genes were upregulated and hypomethylated, including an estrogen receptor gene, and 73 genes were downregulated and hypermethylated, including genes involved in antigen presentation and interferon response pathways (HLA-E, IRF8, and RELA). In ILC SBCs, however, only 17 genes were synchronously hypomethylated and upregulated, whereas 46 genes hypermethylated and downregulated. Interestingly, the SBC gene expression signatures closely corresponded with each histological subtype with only 1.51% of genes overlapping between the two histological subtypes. Differential gene expression and DNA methylation signatures are seen in both IDC and ILC SBCs, including genes that are relevant to tumor growth and proliferation. Differences in gene expression signatures corresponding with each histological subtype emphasize the importance of disease subtype-specific evaluations of molecular alterations.

Patterns of Occurrence and Outcomes of Contralateral Breast Cancer: Analysis of SEER Data.

Population-based estimates are lacking for the temporal trends in the contralateral breast cancer (CBC) risk for patients with breast cancer (BC). Data for BC patients diagnosed with CBC were collected from the Surveillance, Epidemiology, and End Results database. CBC incidence was calculated using the Kaplan-Meier method and the temporal trend in CBC incidence was assessed using joinpoint regression. Survival analysis was calculated using propensity scoring (PS) and multivariate Cox regression with a competing risk model. We found that 10,944 of 212,630 patients with early-stage BC were subsequently diagnosed with secondary BC in the contralateral breast. The 5-, 10-, 15-, and 20-year cumulative CBC incidences were 1.9, 4.6, 7.6, and 10.5%, respectively. Being younger (<40 years), black, hormone receptor-negative, and having undergone radiotherapy were correlated with a high risk of CBC occurrence. CBC incidence increased continuously in the first 11 years after the initial cancer diagnosis, and the upward trend slowed from years 11 to 21, and tended to decline from years 21 to 24. CBC diagnosis was significantly and negatively associated with survival. We reported population-based estimates of the CBC occurrence pattern and risk factors. Patients are at high risk of developing CBC in the first 21 years after the initial BC diagnosis.

Improving the management of patients with secondary breast cancer–an holistic nursing approach

Improving the management of patients with secondary breast cancer–an holistic nursing approach

Mo1732 - Secondary Breast, Ovarian and Uterine Cancers after Colorectal Cancer: A Nationwide Population-Based Cohort Study in Korea

Mo1732 - Secondary Breast, Ovarian and Uterine Cancers after Colorectal Cancer: A Nationwide Population-Based Cohort Study in Korea

Regulation of breast cancer induced bone disease by cancer-specific IKKβ.

NFκB is implicated in breast cancer bone metastasis and skeletal remodelling. However, the role of IKKβ, a key component of the canonical NFκB pathway, in the regulation of breast cancer osteolytic metastasis has not been investigated. Here, we describe the cancer-specific contribution of IKKβ to bone metastasis, skeletal tumour growth and osteolysis associated with breast cancer. IKKβ is highly expressed in invasive breast tumours and its level of expression was higher in patients with bone metastasis. IKKβ overexpression in parental MDA-MD-231 breast cancer cells, promoted mammary tumour growth but failed to convey osteolytic potential to these cells in mice. In contrast, IKKβ overexpression in osteotropic sub-clones of MDA-MB-231 cells with differing osteolytic phenotypes increased incidence of bone metastasis, exacerbated osteolysis and enhanced skeletal tumour growth, whereas its knockdown was inhibitory. Functional and mechanistic studies revealed that IKKβ enhanced the ability of osteotropic MDA-MB-231 cells to migrate, increase osteoclastogenesis, and to inhibit osteoblast differentiation via a mechanism mediated, at least in part, by cytoplasmic sequestering of FoxO3a and VEGFA production. Thus, tumour-selective manipulation of IKKβ and its interaction with FoxO3a may represent a novel strategy to reduce the development of secondary breast cancer in the skeleton.

Clinical and histological features of second breast cancers following radiotherapy for childhood and young adult malignancy.

The purpose of this study was to determine the characteristics of early second breast cancer (SBC) among survivors of childhood and young adult malignancy treated with irradiation. We conducted a multicenter retrospective study of women who presented with breast cancer aged 50 years or younger in nine French centers. 121 patients and 141 SBC were analyzed (invasive = 130; non-invasive = 11). The mean age at first cancer diagnosis was 15 years and at initial SBC diagnosis was 38 years. Bilateral disease before the age of 51 years was diagnosed in 16% of the females. The majority of SBC were invasive carcinomas (92%). Among the invasive carcinomas, 39% had a histoprognostic score of III, 3.1% overexpressed HER2 and 29% were triple negative. The proportion of triple negative phenotype SBC was higher in patients older at first cancer diagnosis [RR = 1.2, 95% CI(1.1-1.3)]. 94% of triple negative SBCs developed in breast tissue which had received>20 Gy. We found a high proportion of aggressive SBC following thoracic radiotherapy in childhood or early adulthood. Advances in knowledge: SBC screening is recommended by scientific societies for these child/young-adulthood cancer survivors in the same way as the one for high risk women because of constitutional mutations. Our results support these recommendations, not only because of a similar cumulative risk, but also because of the aggressive histological characteristics.

WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer

BackgroundMetastatic spread is responsible for the majority of cancer-associated deaths. The tumour microenvironment, including hypoxia, is a major driver of metastasis. The aim of this study was to investigate the role of the E3 ligase WSB-1 in breast cancer biology in the context of the hypoxic tumour microenvironment, particularly regarding metastatic spread.MethodsIn this study, WSB-1 expression was evaluated in breast cancer cell lines and patient samples. In silico analyses were used to determine the impact of WSB-1 expression on distant metastasis-free survival (DMFS) in patients, and correlation between WSB1 expression and hypoxia gene expression signatures. The role of WSB-1 on metastasis promotion was evaluated in vitro and in vivo.ResultsHigh WSB1 expression was associated with decreased DMFS in ER-breast cancer and PR-breast cancer patients. Surprisingly, WSB1 expression was not positively correlated with known hypoxic gene expression signatures in patient samples. Our study is the first to show that WSB-1 knockdown led to decreased metastatic potential in breast cancer hormone receptor-negative models in vitro and in vivo. WSB-1 knockdown was associated with decreased metalloproteinase (MMP) activity, vascular endothelial growth factor (VEGF) secretion, and angiogenic potential.ConclusionsOur data suggests that WSB-1 may be an important regulator of aggressive metastatic disease in hormone receptor-negative breast cancer. WSB-1 could therefore represent a novel regulator and therapeutic target for secondary breast cancer in these patients.

Patient-reported survivorship care practices and late effects after treatment of Hodgkin (HL) and non-Hodgkin lymphoma (NHL).

119 Background: Multimodal treatment of HL and NHL yields excellent outcomes, however, survivors are at risk for developing myriad late- and long-term effects (LLTEs). We describe survivorship care practices and LLTEs reported by HL/ NHL survivors. Methods: From a convenience sample of 964 HL (37%) and NHL (63%) cancer survivors using a publicly available Internet-based survivorship care plan (SCP) tool between 2011-2016, we examined cancer care and toxicity profile data. Results: Of all survivors, 67% were female and 84% were Caucasian; median age of diagnosis was 28y for HL and 49y for NHL survivors with median fu of 5y and 2y, respectively. 88% were free of cancer, 9% with recurrent or secondary malignancy, and 3% with metastatic disease. Chemotherapy was delivered to 89% of HL and 94% of NHL survivors, and radiation (RT) to 64% and 28%, respectively. Of those receiving RT, 96% (n = 217) HL and 61% (n = 106) NHL survivors received chest/mantle RT. Few reported receipt of previous SCP (13%) or treatment summary (4%). Most reported continued care from an oncologist (49%) or in combination with a PCP (19%). A shift to PCP management alone was observed, increasing from 2% of survivors if &lt; 2y fu to 30% once ≥2y fu. Survivors who received chest RT reported: hyper- or hypothyroidism (35%), thyroid nodules (8%), speaking/swallowing changes (20%), heart disease (14%), pulmonary fibrosis/pneumonitis (12%), and skin cancers within the RT field (9%). 6 of 321 (2%) who received chest RT reported secondary breast cancers, compared to zero in the group not receiving chest RT with median time to breast cancer 20.5y (R 6-32 years). Receipt of chemotherapy was associated with: chronic fatigue (56%), cognitive change (56%), peripheral neuropathy (35%), sexual changes (15% of males, 35% of females), and heart disease (10%). Conclusions: While this population achieves excellent disease outcomes, survivors report a substantial burden of LLTEs, suboptimal delivery of survivorship information, and transitions of care in follow-up. Multiple opportunities thus exist through which SCPs may be used to improve awareness regarding survivorship/ LLTEs and communicate follow-up care plans between survivors and treatment teams.