Suzette Delaloge

Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1

How dying tumor cells get noticed Besides killing tumor cells directly, some chemotherapies, such as anthracyclines, also activate the immune system to kill tumors. Vacchelli et al. discovered that in mice, anthracycline-induced antitumor immunity requires immune cells to express the protein formyl peptide receptor 1 (FPR1). Dendritic cells (DCs) near tumors expressed especially high amounts of FPR1. DCs normally capture fragments of dying tumor cells and use them to activate nearby T cells to kill tumors, but DCs lacking FPR1 failed to do this effectively. Individuals with breast or colon cancer expressing a variant of FPR1 and treated with anthracyclines showed poor metastasis-free and overall survival. Thus, FPR1 may affect anti-tumor immunity in people, too. Science, this issue p. 972 Formyl peptide receptor 1 helps the immune system sense dying tumor cells. Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1−/− mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses.

Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials

BACKGROUNDnTumor-infiltrating lymphocytes (TILs) are emerging as strong prognostic factor for early breast cancer patients, especially in the triple-negative subtype. Here, we aim to validate previous findings on the prognostic role of TIL in the context of two randomized adjuvant trials and to investigate whether lymphocyte infiltrates can predict benefit from adjuvant anthracyclines.nnnPATIENTS AND METHODSnA total of 816 patients enrolled and treated at the Gustave Roussy in the context of two multicentric randomized trials comparing adjuvant anthracyclines versus no chemotherapy were included in the present analysis. Primary end point was overall survival (OS). Hematoxilin and eosin slides of primary tumors were retrieved and evaluated for the percentage of intratumoral (It) and stromal (Str) TIL. Each case was also defined as high-TIL or low-TIL breast cancer adopting previously validated cutoffs.nnnRESULTSnTIL were assessable for 781 of 816 cases. High-TIL cases were more likely grade 3 and estrogen receptor (ER)-negative (P < 0.001). In multivariate analysis, both continuous It-TIL and Str-TIL were strong prognostic factors for OS [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95 P = 0.003; HR 0.89, 95% CI 0.81-0.96, P = 0.005 for It-TIL and Str-TIL, respectively]. The prognostic effect of continuous TIL was limited to triple-negative and HER2-positive patients. Ten-year OS rates were: 89% and 68% for triple-negative high-TIL and low-TIL, respectively (HR 0.44, 95% CI 0.18-1.10, P = 0.07) and 78% and 57% for HER2-positive high-TIL versus low-TIL, respectively (HR 0.46, 95% CI 0.20-1.11, P = 0.08). Either continuous or binary TIL variables did not predict for the efficacy of anthracyclines. Test for interaction P value was not significant in the whole study population and in subgroups (ER+/HER2-, HER2+, ER-/HER2-).nnnCONCLUSIONSnWe confirmed the prognostic role of TIL in triple-negative early breast cancer and suggested a prognostic impact in HER2+ patients as well. Basing on our data, TIL should not be used as a parameter to select patients for anthracyclines chemotherapy.

Biology-Driven Phase II Trials: What Is the Optimal Model for Molecular Selection?

The number of newly discovered oncogenic molecular alterations has increased dramatically during recent years. A large number of such relevant oncogenic molecular alterations occur in a small percentage of patients and define a specific segment of the disease. Disease segmentation in rare molecular entities is also related to a combination of frequent events. For example, ERBB2 amplification and PIK3CA mutations coexist in about 2% of breast cancers and could define a trastuzumab-resistant phenotype. Overall, this introduction emphasizes that each frequent cancer type could, in fact, be subdivided into several rare molecular diseases according to relevant oncogenic events. This segmentation into rare molecular diseases may have major implications for early drug development.

Chk1 as a new therapeutic target in triple-negative breast cancer

OBJECTIVESnBioinformatics analyses of pathways and genes differentially expressed between malignant and benign lesions could allow discovering new therapeutic targets. Here, we identified Checkpoint kinase 1 (Chk1) as a potent therapeutic target in triple-negative breast cancer (TNBC).nnnMATERIALS AND METHODSnDifferential gene expression between TNBC, other malignant and benign lesions was performed on two breast cancer datasets. Chk1 was targeted using RNA interference or chemical inhibitor in several TNBC cell lines.nnnRESULTSnDNA repair pathway was identified as one mostly deregulated pathway in TNBC as compared to benign lesions. Chk1 was identified as candidate target among the 35 genes included in this pathway. Gene expression analysis revealed that Chk1 gene was significantly overexpressed in TNBC as compared to non-TNBC and benign lesions. Depletion of Chk1 protein expression induced a marked reduction of cell viability and led to mitotic catastrophe in TNBC cells. Chemical Chk1 inhibitor decreased survival in TNBC cells, and transcriptome analyze revealed a modulation of gene expression profile in response to Chk1 treatment.nnnCONCLUSIONnThese findings suggest that Chk1 may represent a therapeutic target in TNBC, and provide a rationale to evaluate Chk1 inhibitors in breast cancer patients.

Quantification of residual risk of relapse in breast cancer patients optimally treated

Despite remarkable improvements in breast cancer survival in the last decades, a proportion of patients still relapse after treatment for early disease. Different prognostic parameters may permit to roughly quantify the residual risk of relapse after (neo)adjuvant therapy. They include: tumor stage and classical molecular features at baseline, newly proposed prognosticators (such as tumor-infiltrating lymphocytes and integrated genomic tools) and the evaluation of tumor response after primary systemic therapy. However, the performance of these factors is still suboptimal and should be improved. Further research aimed to discover new possible prognostic factors in patients who received optimal systemic therapy is needed. Moreover, to exploit at the best the potential of each of these parameters, they should be integrated into algorithms to guide treatment decisions and to select those patients who may deserve the inclusion in clinical trials.

Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers.

BACKGROUNDnMolecular segmentation of breast cancer allows identification of small groups of patients who present high sensitivity to targeted agents. A patient, with chemo- and trastuzumab-resistant HER2-overexpressing breast cancer, who presented concomitant acute promyelocytic leukemia, showed a response in her breast lesions to retinoic acid, arsenic, and aracytin. We therefore investigated whether RARA gene amplification could be associated with sensitivity to retinoic acid derivatives in breast cancers.nnnMATERIALS AND METHODSnArray comparative genomic hybridization and gene expression arrays were used to characterize RARA amplifications and expression in 103 breast cancer samples. In vitro activity of ATRA was characterized in T47D, SKBR3, and BT474 cell lines.nnnRESULTSnRetinoic acid receptor alpha was gained or amplified in 27% of HER2-positive and 13% of HER2-negative breast cancer samples. Retinoic acid receptor alpha can be coamplified with HER2. Retinoic acid receptor alpha copy number changes could be correlated with messenger RNA expression. All-trans-retinoic acid reduced cell viability of RARA-amplified, but not RARA-normal, cell lines through apoptosis. Gene expression arrays showed that ATRA-induced apoptosis in RARA-amplified cell lines was related to an increase in CASP1 and IRF1.nnnCONCLUSIONnThe results of this study suggest that breast cancers exhibiting RARA amplifications could be sensitive to retinoic acid. A phase II trial will evaluate this hypothesis in the clinical setting.

Effect of PALB2 status on breast cancer precision medicine

598 www.thelancet.com/oncology Vol 16 June 2015 both be considered carefully. Chang and colleagues state that lobectomy with dissection or sampling of mediastinal lymph nodes (ie, intraoperative dissection of whole lymph nodes, either all that are accessible or those in specifi ed anatomical locations) is the standard of care for operable, stage I, non-small-cell lung cancer. However, after surgical lobectomy— when all mediastinal nodes can be looked at under the microscope—some cases will be identifi ed as non-stage-I cancers. But, in a cohort of patients treated with SABR, these cases would remain, thus systematically defeating the intention-to-treat principle and providing a golden opportunity to bias the analysis in favour of lobectomy. The clinical eff ectiveness of the addition of lymphadenectomy to lobectomy has not been proven. The notion runs counter to the evidence gained in breast cancer, in which the historical justifi cation for axillary node dissection and clearance has been reversed. In lung cancer, lymphadenectomy is being promoted without evidence of effi cacy in an era in which such changes in standards of care should be tested with randomised controlled trials. The opportunity of a fair test should be given to less invasive treatments. With an average age of 67 years, the patients in Chang and colleagues’ study were not particularly elderly, but cancer treatments are being off ered to ever-older patients who might not feature in trials and for whom improved evidence is needed. SABR is not the only candidate procedure that might reduce the harms of lung cancer treatment without loss of eff ectiveness. The uptake of videothoracoscopy, for example, has been resisted by surgeons, but the accumulating case series and registry evidence suggest that oncological eff ectiveness is not sacrifi ced by moving away from thoracotomy. The VIOLET trial in the UK seeks to test that question in a randomised controlled trial. Clinicians have an ethical imperative to obtain evidence rather than continue to perpetrate needless harm through ignorance. “Trust me, I’m your doctor” does not have the ring of truth when diff erent doctors claim to know what is best while consistently failing to encourage trials to put their beliefs to the test, as evidenced by poor recruitment into studies. Patients, too, have a societal duty to participate in carefully planned and monitored trials. However, evidence suggests that patients are not the main obstacle to trial recruitment; many are willing to participate in studies for various motives, including altruism.

The horizon of precision medicine in breast cancer: fragmentation, alliance, or reunification?

Genomic studies have shown that breast cancer includes a large number of targetable genomic alterations. Most of these genomic alterations are rare and can evolve during the natural history of the disease. Three paths are being followed to develop precision medicine in metastatic breast cancer. First, the conventional path will consist of fragmenting the disease and developing drugs in each rare genomic segment. This will require screening large numbers of patients for genomic alterations to run the therapeutic trials, especially the registration trials. The second path will consist in clustering rare genomic alterations in more frequent segments defined by an altered pathway. Finally, one possible path for precision medicine will be to test genomic algorithms for the whole patient population with metastatic breast cancer. This latter scenario would reunify breast cancer into a single entity and test whether the use of genomics would improve outcomes in this population of patients. Challenges and perspective in the field of precision medicine will include the prediction of resistance, the integration of immunology, and DNA repair in the genomic algorithms and the transfer of concepts to early-stage breast cancers.