Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine ...the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer.
We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing.
Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0–9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% 95% CI 94·5–98·4 vs 96·6% 95·8–97·3; at 5 years: 83·8% 79·3–87·5 vs 85·0% 83·5–86·4; at 10 years: 73·4% 67·4–78·5 vs 70·1% 67·7–72·3; hazard ratio HR 0·96 95% CI 0·76–1·22; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% 95% CI 89–97 vs 91% 88–94; HR 0·59 95% CI 0·35–0·99; p=0·047) but not 5 years (81% 73–87 vs 74% 70–78; HR 1·13 0·70–1·84; p=0·62) or 10 years (72% 62–80 vs 69% 63–74; HR 2·12 0·82–5·49; p= 0·12).
Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences.
Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.
Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin’s role in ...cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.
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•Metformin enhances antitumor CTL immunity by blocking PD-L1/PD-1 axis•Metformin-activated AMPK directly binds to and phosphorylates PD-L1 at S195•Abnormal PD-L1 glycosylation induced by pS195 leads to PD-L1 degradation by ERAD•Combination therapy with metformin and anti-CTLA4 has a synergistic antitumor effect
Cha et al. elucidated a mechanism to show that metformin-activated AMPK phosphorylates PD-L1 at S195 to induce abnormal glycosylation and degrades PD-L1 through an ERAD pathway. This study suggests the potential to use metformin as an adjuvant with various non-PD-L1/PD-1-targeting immune therapies.
Modern approaches, including hypofractionation or partial breast irradiation for selected women, might lessen the adverse effects of radiotherapy while maintaining or improving the benefits. ......radiation-induced second cancers of the lung and oesophagus or angiosarcoma might follow previous breast cancer radiotherapy. Two-thirds of patients endure symptoms, including chronic pain, months later. ...what should one do for a patient already on the emotional rollercoaster of conflicting views, information, and options, including whether to undergo mastectomy or breast conservation with radiotherapy? Guiding patients to an informed, individual plan of treatment, whichever option they might choose, remains one of the challenges of modern clinical practice. shutterstock.com/srisakorn wonglakorn For more on total mastectomy versus breast-conserving treatment see N Engl J Med 2002; 347: 1233–41 For more on partial breast irradiation see Pract Radiat Oncol 2017; 7: 73–79 For more on radiation-induced second cancers see Radiother Oncol 2015; 114: 56–65 For more on the risk of cardiac complications of radiotherapy for breast cancer see Nat Rev Clin Oncol 2013; 10: 310–12 For more on the risk of ischaemic heart disease see N Engl J Med 2013; 368: 987–98 For more on volume incident learning system data for radiotherapy process reliability see Pract Radiat Oncol 2019; 9: e210–17 For more on the costs and complications of breast-conserving surgery see JAMA Surg 2017; 152: 1084–86 For more on the late-term symptoms after breast-conserving surgery see Pain 2014; 155: 232–43 I declare no competing interests Acknowledgments I thank Donna Pinto, Deb Collyar, Anne Meyn, and Susan Rafte and patient advocates for advice in preparing this Spotlight.
To update the accelerated partial breast irradiation Consensus Statement published in 2009 and provide guidance on use of intraoperative radiation therapy (IORT) for partial breast irradiation in ...early-stage breast cancer, based on published evidence complemented by expert opinion.
A systematic PubMed search using the same terms as the original Consensus Statement yielded 419 articles; 44 articles were selected. The authors synthesized the published evidence and, through a series of conference calls and e-mails, reached consensus regarding the recommendations.
The new recommendations include lowering the age in the "suitability group" from 60 to 50 years and in the "cautionary group" to 40 years for patients who meet all other elements of suitability (Table 1). Patients with low-risk ductal carcinoma in situ, as per Radiation Therapy Oncology Group 9804 criteria, were categorized in the "suitable" group. The task force agreed to maintain the current criteria based on margin status. Recommendations for the use of IORT for breast cancer patients include: counseling patients regarding the higher risk of ipsilateral breast tumor recurrence with IORT compared with whole breast irradiation; the need for prospective monitoring of long-term local control and toxicity with low-energy radiograph IORT given limited follow-up; and restriction of IORT to women with invasive cancer considered "suitable."
These recommendations will provide updated clinical guidance regarding use of accelerated partial breast irradiation for radiation oncologists and other specialists participating in the care of breast cancer patients.
Metformin, an oral biguanide widely used to treat diabetes, has considerable potential and is in clinical trials as an experimental preventive or therapeutic agent for a range of cancers. Direct ...actions targeting cellular pathways, particularly via AMP-activated protein kinase and through inhibiting mitochondrial ATP synthesis, or systemic mechanisms involving insulin and insulin-like growth factors have been much studied in vitro and in preclinical models. Epidemiologic and retrospective studies also provide clinical evidence in support of metformin as an antitumor agent. Preoperative window-of-opportunity trials confirm the safety of metformin in women with primary breast cancer, and demonstrate reduction in tumor cell proliferation and complex pathways of gene suppression or overexpression attributable to metformin. Confirmation of insulin-mediated effects, independent of body mass index, also supports the potential benefit of adjuvant metformin therapy. Neoadjuvant, adjuvant, and advanced disease trials combining metformin with established anticancer agents are under way or proposed. Companion biomarker studies will utilize in vitro and preclinical understanding of the relevant molecular pathways to, in future, refine patient and tumor selection for metformin therapy.
Ductal carcinoma in situ (DCIS)—a significant precursor to invasive breast cancer—is typically diagnosed as microcalcifications in mammograms. However, the effective use of mammograms and other ...patient data to plan treatment has been restricted by our limited understanding of DCIS growth and calcification. We develop a mechanistic, agent-based cell model and apply it to DCIS. Cell motion is determined by a balance of biomechanical forces. We use potential functions to model interactions with the basement membrane and amongst cells of unequal size and phenotype. Each cell's phenotype is determined by genomic/proteomic- and microenvironment-dependent stochastic processes. Detailed “sub-models” describe cell volume changes during proliferation and necrosis; we are the first to account for cell calcification.
We introduce the first patient-specific calibration method to fully constrain the model based upon clinically-accessible histopathology data. After simulating 45 days of solid-type DCIS with comedonecrosis, the model predicts: necrotic cell lysis acts as a biomechanical stress relief and is responsible for the linear DCIS growth observed in mammography; the rate of DCIS advance varies with the duct radius; the tumour grows 7–10mm per year—consistent with mammographic data; and the mammographic and (post-operative) pathologic sizes are linearly correlated—in quantitative agreement with the clinical literature. Patient histopathology matches the predicted DCIS microstructure: an outer proliferative rim surrounds a stratified necrotic core with nuclear debris on its outer edge and calcification in the centre. This work illustrates that computational modelling can provide new insight on the biophysical underpinnings of cancer. It may 1day be possible to augment a patient's mammography and other imaging with rigorously-calibrated models that help select optimal surgical margins based upon the patient's histopathologic data.
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► We introduce the first patient-specific calibration to individual pathology data. ► Biomechanics of necrotic cell lysis leads to linear growth at 7.5–10.2mm/year. ► The model predicts a linear correlation between the mammography and pathology sizes. ► The predicted layered necrotic core microstructure gives new insights on mammography. ► Key model predictions are quantitatively validated to pathology and radiology data.
Chronic postsurgical pain (CPSP) is a common postoperative adverse event affecting up to half of women undergoing breast cancer surgery, yet few epidemiological studies have prospectively ...investigated the role of preoperative, intraoperative, and postoperative risk factors for pain onset and chronicity. We prospectively investigated preoperative sociodemographic and psychological factors, intraoperative clinical factors, and acute postoperative pain in a prospective cohort of 362 women undergoing surgery for primary breast cancer. Intraoperative nerve handling (division or preservation) of the intercostobrachial nerve was recorded. At 4 and 9months after surgery, incidence of chronic painful symptoms not present preoperatively was 68% and 63%, respectively. Univariate analysis revealed that multiple psychological factors and nerve division was associated with chronic pain at 4 and 9months. In a multivariate model, independent predictors of CPSP at 4months included younger age and acute postoperative pain (odds ratio OR 1.34, 95% confidence interval CI 1.12 to 1.60), whereas preoperative psychological robustness (OR 0.70, 95% CI 0.49 to 0.99), a composite variable comprising high dispositional optimism, high positive affect, and low emotional distress, was protective. At 9months, younger age, axillary node clearance (OR 2.97, 95% CI 1.09 to 8.06), and severity of acute postoperative pain (OR 1.17, 95% CI 1.00 to 1.37) were predictive of pain persistence. Of those with CPSP, 25% experienced moderate to severe pain and 40% were positive on Douleur Neuropathique 4 and Self-Complete Leeds Assessment of Neuropathic Symptoms and Signs pain scales. Overall, a high proportion of women report painful symptoms, altered sensations, and numbness in the upper body within the first 9months after resectional breast surgery and cancer treatment.
Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational ...processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.
HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or ...death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment.
We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II–III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0–1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m2; carboplatin area under the concentration–time curve 6 mg/mL × min; trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab same dosing as in the other group). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing.
Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference −11·3 percentage points, 95% CI −20·5 to −2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3–4 adverse event (29 13% of 223 vs 141 64% of 219) or a serious adverse event (11 5% of 223 vs 63 29% of 219). The most common grade 3–4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three 1% of 223 patients vs 11 5% of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three 1% vs seven 3%), alanine aminotransferase increase (three 1% vs four 2%), and hypokalaemia (three 1% vs five 2%). The most common grade 3–4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 25% of 219 vs one <1% of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 15% vs 2 <1%), and febrile neutropenia (33 15% vs 0). No deaths were reported during neoadjuvant treatment.
Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3–4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted.
F Hoffmann-La Roche and Genentech.
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