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International audience; A common practice in many auctions is to offer bidders an opportunity to improve their bids, known as a best and final offer stage. This improved bid can depend on new information either about the asset or about the competitors. This paper examines the effects of new information regarding competitors, seeking to determine what information the auctioneer should provide assuming the set of allowable bids is discrete. The rational strategy profile that maximizes the revenue of the auctioneer is the one where each bidder makes the highest possible bid that is lower than his valuation of the item. This strategy profile is an equilibrium for a large enough number of bidders, regardless of the information released. We compare the number of bidders needed for this profile to be an equilibrium under different information structures. We find that it becomes an equilibrium with fewer bidders when less additional information is made available to the bidders regarding the competition. It follows that when the number of bidders is a priori unknown, there are some advantages to the auctioneer not revealing information and conducting a one-stage auction instead.

Supplementary Material

Adaptive therapy seeks to exploit intratumoral competition to avoid, or at least delay, the emergence of therapy resistance in cancer. Motivated by promising results in prostate cancer, there is growing interest in extending this approach to other neoplasms. As such, it is urgent to understand the characteristics of a cancer that determine whether or not it will respond well to adaptive therapy. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this article, we study a general, but simple, mathematical model to investigate whether the presence of a cost is necessary for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. Tumor cells were divided into sensitive and resistant populations and we model their competition using a system of two ordinary differential equations based on the Lotka–Volterra model. For tumors close to their environmental carrying capacity, a cost was not required. However, for tumors growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, it is important to consider cell turnover in the tumor, and we discuss its role in modulating the impact of a resistance cost. To conclude, we present evidence for the predicted cost–turnover interplay in data from 67 patients with prostate cancer undergoing intermittent androgen deprivation therapy. Our work helps to clarify under which circumstances adaptive therapy may be beneficial and suggests that turnover may play an unexpectedly important role in the decision-making process.Significance:Tumor cell turnover modulates the speed of selection against drug resistance by amplifying the effects of competition and resistance costs; as such, turnover is an important factor in resistance management via adaptive therapy.See related commentary by Strobl et al., p. 811

Stackelberg evolutionary game (SEG) theory combines classical and evolutionary game theory to frame interactions between a rational leader and evolving followers. In some of these interactions, the leader wants to preserve the evolving system (e.g. fisheries management), while in others, they try to drive the system to extinction (e.g. pest control). Often the worst strategy for the leader is to adopt a constant aggressive strategy (e.g. overfishing in fisheries management or maximum tolerable dose in cancer treatment). Taking into account the ecological dynamics typically leads to better outcomes for the leader and corresponds to the Nash equilibria in game-theoretic terms. However, the leader’s most profitable strategy is to anticipate and steer the eco-evolutionary dynamics, leading to the Stackelberg equilibrium of the game. We show how our results have the potential to help in fields where humans try to bring an evolutionary system into the desired outcome, such as, among others, fisheries management, pest management and cancer treatment. Finally, we discuss limitations and opportunities for applying SEGs to improve the management of evolving biological systems. This article is part of the theme issue ‘Half a century of evolutionary games: a synthesis of theory, application and future directions’.

Adaptive therapy is a dynamic cancer treatment protocol that updates (or ‘adapts’) treatment decisions in anticipation of evolving tumor dynamics. This broad term encompasses many possible dynamic treatment protocols of patient-specific dose modulation or dose timing. Adaptive therapy maintains high levels of tumor burden to benefit from the competitive suppression of treatment-sensitive subpopulations on treatment-resistant subpopulations. This evolution-based approach to cancer treatment has been integrated into several ongoing or planned clinical trials, including treatment of metastatic castrate resistant prostate cancer, ovarian cancer, and BRAF-mutant melanoma. In the previous few decades, experimental and clinical investigation of adaptive therapy has progressed synergistically with mathematical and computational modeling. In this work, we discuss 11 open questions in cancer adaptive therapy mathematical modeling. The questions are split into three sections: (1) integrating the appropriate components into mathematical models (2) design and validation of dosing protocols, and (3) challenges and opportunities in clinical translation.

Characterizing the mode—the way, manner or pattern—of evolution in tumours is important for clinical forecasting and optimizing cancer treatment. Sequencing studies have inferred various modes, including branching, punctuated and neutral evolution, but it is unclear why a particular pattern predominates in any given tumour. Here we propose that tumour architecture is key to explaining the variety of observed genetic patterns. We examine this hypothesis using spatially explicit population genetics models and demonstrate that, within biologically relevant parameter ranges, different spatial structures can generate four tumour evolutionary modes: rapid clonal expansion, progressive diversification, branching evolution and effectively almost neutral evolution. Quantitative indices for describing and classifying these evolutionary modes are presented. Using these indices, we show that our model predictions are consistent with empirical observations for cancer types with corresponding spatial structures. The manner of cell dispersal and the range of cell–cell interactions are found to be essential factors in accurately characterizing, forecasting and controlling tumour evolution., Nature Ecology & Evolution, 6 (2), ISSN:2397-334X

Challenging the paradigm of the maximum tolerated dose, recent studies have shown that a strategy aiming for containment, not elimination, can control tumor burden more effectivelyin vitro, in mouse models, and in the clinic. These outcomes are consistent with the hypothesis that emergence of resistance to cancer therapy may be prevented or delayed by exploiting competitive ecological interactions between drug-sensitive and resistant tumor cell subpopulations. However, although various mathematical and computational models have been proposed to explain the superiority of particular containment strategies, this evolutionary approach to cancer therapy lacks a rigorous theoretical foundation. Here we combine extensive mathematical analysis and numerical simulations to establish general conditions under which a containment strategy is expected to control tumor burden more effectively than applying the maximum tolerated dose. We show that when resistant cells are present, an idealized strategy of containing a tumor at a maximum tolerable size maximizes time to treatment failure (that is, the time at which tumor burden becomes intolerable). These results are very general and do not depend on any fitness cost of resistance. We further provide formulas for predicting the clinical benefits attributable to containment strategies in a wide range of scenarios, and we compare outcomes of theoretically optimal treatments with those of more practical protocols. Our results strengthen the rationale for clinical trials of evolutionarily-informed cancer therapy.

Adaptive therapy seeks to exploit intratumoral competition to avoid, or at least delay, the emergence of therapy resistance in cancer. Motivated by promising results in prostate cancer, there is growing interest in extending this approach to other neoplasms. As such, it is urgent to understand the characteristics of a cancer that determine whether or not it will respond well to adaptive therapy. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this article, we study a general, but simple, mathematical model to investigate whether the presence of a cost is necessary for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. Tumor cells were divided into sensitive and resistant populations and we model their competition using a system of two ordinary differential equations based on the Lotka–Volterra model. For tumors close to their environmental carrying capacity, a cost was not required. However, for tumors growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, it is important to consider cell turnover in the tumor, and we discuss its role in modulating the impact of a resistance cost. To conclude, we present evidence for the predicted cost–turnover interplay in data from 67 patients with prostate cancer undergoing intermittent androgen deprivation therapy. Our work helps to clarify under which circumstances adaptive therapy may be beneficial and suggests that turnover may play an unexpectedly important role in the decision-making process. Significance: Tumor cell turnover modulates the speed of selection against drug resistance by amplifying the effects of competition and resistance costs; as such, turnover is an important factor in resistance management via adaptive therapy. See related commentary by Strobl et al., p. 811

Recent studies have shown that a strategy aiming for containment, not elimination, can control tumour burden more effectively in vitro, in mouse models and in the clinic. These outcomes are consistent with the hypothesis that emergence of resistance to cancer therapy may be prevented or delayed by exploiting competitive ecological interactions between drug-sensitive and drug-resistant tumour cell subpopulations. However, although various mathematical and computational models have been proposed to explain the superiority of particular containment strategies, this evolutionary approach to cancer therapy lacks a rigorous theoretical foundation. Here we combine extensive mathematical analysis and numerical simulations to establish general conditions under which a containment strategy is expected to control tumour burden more effectively than applying the maximum tolerated dose. We show that containment may substantially outperform more aggressive treatment strategies even if resistance incurs no cellular fitness cost. We further provide formulas for predicting the clinical benefits attributable to containment strategies in a wide range of scenarios and compare the outcomes of theoretically optimal treatments with those of more practical protocols. Our results strengthen the rationale for clinical trials of evolutionarily informed cancer therapy, while also clarifying conditions under which containment might fail to outperform standard of care. Adaptive therapies based on evolutionary principles propose that, under certain conditions, tumour containment, rather than elimination, might be the best strategy to treat cancer. This study presents a theoretical analysis of different models of tumour containment.

In the absence of curative therapies, treatment of metastatic castrate-resistant prostate cancer (mCRPC) using currently available drugs can be improved by integrating evolutionary principles that govern proliferation of resistant subpopulations into current treatment protocols. Here we develop what is coined as an ‘evolutionary stable therapy’, within the context of the mathematical model that has been used to inform the first adaptive therapy clinical trial of mCRPC. The objective of this therapy is to maintain a stable polymorphic tumor heterogeneity of sensitive and resistant cells to therapy in order to prolong treatment efficacy and progression free survival. Optimal control analysis shows that an increasing dose titration protocol, a very common clinical dosing process, can achieve tumor stabilization for a wide range of potential initial tumor compositions and volumes. Furthermore, larger tumor volumes may counter intuitively be more likely to be stabilized if sensitive cells dominate the tumor composition at time of initial treatment, suggesting a delay of initial treatment could prove beneficial. While it remains uncertain if metastatic disease in humans has the properties that allow it to be truly stabilized, the benefits of a dose titration protocol warrant additional pre-clinical and clinical investigations.

Bladder cancer is the 9th most commonly diagnosed cancer. Nearly half of patients with early stage bladder cancer treated with the immune-stimulating agent BCG have disease recurrence, while 13% progress to invasive bladder cancer. Here we explored the potential of tumor mutational heterogeneity and the role of pro- and anti-inflammatory cytokines to identify different subtypes of bladder cancer that may predict therapeutic response to BCG. Further, we used mathematical modeling of dosing strategies to infer tumor response to varying doses and time schedules f BCG administration. As a proof-of-concept, present adaptive therapy scheduling of BCG as a viable strategy to control tumor size and minimize recurrence.

The fitness of an evolutionary individual can be understood in terms of its two basic components: survival and reproduction. As embodied in current theory, trade-offs between these fitness components drive the evolution of life-history traits in extant multicellular organisms. Here, we argue that the evolution of germ-soma specialization and the emergence of individuality at a new higher level during the transition from unicellular to multicellular organisms are also consequences of trade-offs between the two components of fitness-survival and reproduction. The models presented here explore fitness trade-offs at both the cell and group levels during the unicellular-multicellular transition. When the two components of fitness negatively covary at the lower level there is an enhanced fitness at the group level equal to the covariance of components at the lower level. We show that the group fitness trade-offs are initially determined by the cell level trade-offs. However, as the transition proceeds to multicellularity, the group level trade-offs depart from the cell level ones, because certain fitness advantages of cell specialization may be realized only by the group. The curvature of the trade-off between fitness components is a basic issue in life-history theory and we predict that this curvature is concave in single-celled organisms but becomes increasingly convex as group size increases in multicellular organisms. We argue that the increasingly convex curvature of the trade-off function is driven by the initial cost of reproduction to survival which increases as group size increases. To illustrate the principles and conclusions of the model, we consider aspects of the biology of the volvocine green algae, which contain both unicellular and multicellular members.

International audience; We provide a discipline for belief formation through a model of subjective beliefs, in which agents hold strategic beliefs. More precisely, we consider beliefs as a strategic variable that agents can choose (consciously or not) in order to maximize their utility at the equilibrium. These strategic beliefs result from an evolutionary process. We find that evolutionary strategic behavior leads to belief subjectivity and heterogeneity. Optimism (resp. overconfidence) as well as pessimism (resp. doubt) both emerge from the evolution process. Furthermore, we obtain a positive correlation between pessimism (rep. doubt) and risk-tolerance. We analyse the equilibrium characteristics. Under reasonable assumptions, the consensus belief is pessimistic and, as a consequence, the risk premium is higher than in a standard setting.

Why do investors keep different opinions even though they learn from their own failures and successes? Why do investors keep different opinions even though they observe each other and learn from their relative failures and successes? We analyze beliefs dynamics when beliefs result from a very general learning process that favors beliefs leading to higher absolute or relative utility levels. We show that such a process converges to the Nash equilibrium in a game of strategic belief choices. The asymptotic beliefs are subjective and heterogeneous across the agents. Optimism (respectively overconfidence) as well as pessimism (respectively doubt) emerge from the learning process. Furthermore, we obtain a positive correlation between pessimism (respectively doubt) and risk tolerance. Under reasonable assumptions, beliefs exhibit a pessimistic bias and, as a consequence, the risk premium is higher than in a standard setting. Copyright 2013, Oxford University Press.

International audience; Potential based no-regret dynamics are shown to be related to fictitious play. Roughly, these are epsilon-best reply dynamics where epsilon is the maximal regret, which vanishes with time. This allows for alternative and sometimes much shorter proofs of known results on convergence of no-regret dynamics to the set of Nash equilibria.

We survey and unify results on elimination of dominated strategies by monotonic dynamics and prove some new results that may be seen as dual to those of Hofbauer and Weibull (J. Econ. Theory, 1996, 558-573) on convex monotonic dynamics.

The dual reduction process, introduced by Myerson, allows to reduce a finite game into a smaller dimensional game such that any equilibrium of the reduced game is an equilibrium of the original game. This holds both for Nash equilibrium and correlated equilibrium. We present examples of applications of dual reduction and argue that this is a useful tool to study Nash equilibria and correlated equilibria. We then investigate its properties., This is a revised version of the cahier du laboratoire d'\'econom\'etrie 2003-31

International audience; We study the structure of the set of equilibrium payoffs in finite games, both for Nash equilibrium and correlated equilibrium. A nonempty subset of R^2 is shown to be the set of Nash equilibrium payoffs of a bimatrix game if and only if it is a finite union of rectangles. Furthermore, we show that for any nonempty finite union of rectangles U and any polytope P in R^2 containing U, there exists a bimatrix game with U as set of Nash equilibrium payoffs and P as set of correlated equilibrium payoffs. The n-player case and the robustness of this result to perturbation of the payoff matrices are also studied.

International audience; We investigate whether having a unique equilibrium (or a given number of equilibria) is robust to perturbation of the payoffs, both for Nash equilibrium and correlated equilibrium. We show that the set of n-player finite games with a unique correlated equilibrium is open, while this is not true of Nash equilibrium for n>2. The crucial lemma is that a unique correlated equilibrium is a quasi-strict Nash equilibrium. Related results are studied. For instance, we show that generic two-person zero-sum games have a unique correlated equilibrium and that, while the set of symmetric bimatrix games with a unique symmetric Nash equilibrium is not open, the set of symmetric bimatrix games with a unique and quasi-strict symmetric Nash equilibrium is.

This note establishes that in every 3-3 symmetric game, the replicator dynamics eliminates all strategies that are never used in correlated equilibrium. This extends to the best-response dynamics and to any convex monotonic dynamics. The proof is based on dual reduction., Cette note établit que dans tous les jeux 3-3 symmetriques, la dynamique des réplicateurs élimine toutes les stratégies qui ne sont utilisées dans aucun équilibre corrélé. Ce résultat s'étend à la dynamique de meilleure réponse et à toutes les dynamiques convexes monotones. La preuve repose sur des arguments de réduction duale..